Issues in TB Drug Development: TB/HIV

Issues in TB Drug Development: TB/HIV Open Forum Gavin Churchyard 18 th August 2010

Presentation outline TB/HIV Epidemiology clinical aspects HIV associated TB Drug-Drug interactions Immunotherapy Latent TB infection New drugs TB vaccines Conclusion NO more people living with HIV dying of TB

SA has one of the worst TB epidemics in the world! Ranked 5 th globally 4 th greatest number of MDR TB patients Most number of HIV positive TB patients in the world 70% of TB cases HIV co-infected XDR TB Largely HIV associated Very high mortality

Integrated TB and HIV treatment SAPIT trial saves lives Integrated TB & HIV treatment reduced mortality by 56% in HIV-infected TB patients with CD4 counts<500 cells/ml 3 CAMELIA trial Early ART initiation (after 2 weeks) in severely immuno-suppressed HIV-infected Cambodian TB patients significantly reduced mortality (Karim et al. NEJM. 2010, FX Blanc. THLBB1. AIDS2010)

Projected use of PI-based ART 200000 Person-years on protease inhibitors 180000 160000 140000 120000 100000 80000 60000 40000 20000 0 2009 2010 2011 2012 2013 2014 Argentina Botswana Brazil Cameroon China Cote d'ivoire Ethiopia ADULTS - failed 1 st line ART Infants and young children - 1 st line Data courtesy of Drs D Ripin and M O Brien (CSHOR), Clinton Health Access Initiative [ 05.01.2010]. India Kenya Malawi Mexico Mozambique Namibia Nigeria Rwanda South Africa Tanzania Thailand Uganda Zambia Zimbabwe GLOBAL TOTAL/10

Efficacy of TB preventive therapy among HIV-infected individuals TB Death Reference PPD+ 0.38 1.0 1.0 0.8 PPD- 0.83 1.02 PPD-unknown 0.81 0.84 Overall 0.64 0.95 Relative Risk (Fixed) & 95% CI Woldehanna 2004, Cochrane review

Effect of IPT and ART on TB incidence and mortality Golub. AIDS.2008 Incidence /100py ahr (95% CI) No IPT/ART 7.1 1 ART 4.6 0.36 (0.25-0.5) ART/IPT 1.1 0.11 (0.02-0.8) Innes. CROI 2010 Mortality/100py ahr (95% CI) ART 11.1 1 ART/IPT 3.5 0.47 (0.3-0.7)

Reduction in TB incidence with 36 vs 6 months IPT Author Location Intention to treat Martinson Soweto 19% 69% Per Protocol Samandari Botswana All 54% 65% TST+ 93% TST- 19% (Martinson et al. Union conference, 2008, CROI 2009) (Samandari et al. Union Conference. 2009)

New drugs & regimens required for HIV associated TB To increase Efficacy Safety tolerability To decrease treatment duration Complexity drug-drug interactions cost

Rifapentine food interactions 30 14 25 12 RFP plasma conc. (mg/l) 20 15 10 5 +86% (%RSE=20) 25-DRFP plasma conc. (mg/l) 10 8 6 4 2 High fat meal Bulk_Low fat meal Bulk_High fat Chicken soup Fasted state 0 0 10 20 30 40 50 60 0 0 10 20 30 40 50 60 Time after dose (h) Time after dose (h) Zvada SP. Antimicrob Agents Chemother. 2010; 54(8):3390-4

Antimicrob Agents Chemother 2007, 51:2861 6 and 2008, 52:4037-42; J Antimicrob Chemother. 2007; 60:1398-401; Clin Infect Dis 2007, 45:1001 7. J Int. AIDS Soc. 2008, 11: S95 (abstr); J Infect 2008: 57, 78-81 Potential interactions b/w fluroquinolones and antiretrovirals Safety interactions QT prolongation (LPV/r) Dysglycaemia (PIs) PK interactions chelation by multivalent anions (buffered ddi) moxifloxacin is a UGT, SGT substrate

PXR: regulates drug-metabolizing enzymes BL AP PHASE II UGT s GST s SULTs MDR1 PHASE I CYP2B6 CYP2C8 CYP3A4 CYP2B9 CYP2C9 CYP3A7 PXR MRP2 OATP2 EFFLUX TRANSPORTERS INFLUX OATP1B1 BASELINE ACTIVITY: PXR expression enzymes activity & transporters Pharmacogenomics 2008, 9: 1695 1709. Drug Metab Dispos 2006, 10:1756-63 & 2007, 35:1400-7.)

Rifampicin is a potent activator of PXR BL AP UGT s CYP2B6 CYP2C8 CYP3A4 GST s CYP2B9 CYP2C9 CYP3A7 SULTs PXR- RXR RIF. MDR1 MRP2 OATP2 OATP1B1 DRUG Activating ligands trigger altered expression of multiple of enzymes and transporters, with compound effects on substrate concentrations. J Pharmacol Exp Ther 2003, 304: 223-28

Drug-Drug Interactions Drug Diarylquinolines (TMC207) Ethylene Diamines (SQ-109) Nitroimidazoles (PA-824, OPC-67683) oxazolidinones (PNU-100480, Linezolid ) Interactions CYP 3A4 Substrate No PK interactions with H/Z PK studies with EFV, NVP, LPV/r awaited CYP 2D6 / CYP 2C19 substrate Not metabolized by or interfere with CYP enzymes Mono Aminine Oxidase Inhibitors Not metabolized by or interfere with drug metabolizing enzymes (Source: H McIlleron)

Combined toxicities Example of Linezolid CNS toxicity Peripheral neuropathy Lactic acidosis Myelosuppression EFV DDI, D4T D4T ZDV (Source: H McIlleron)

Role of adjunctive immunotherapy Shortening the duration of TB treatment Improve treatment success of M(X)DR TB Reduce clinical complications Reduce rate of recurrent TB

Immunotherapy that Enhance protective immunity and/or down-regulate Th2 activity GMP manufacturing capacity exists IvIg HE2000 M. vaccae anti-il-4 RUTI GMP capacity to be established hsp65 DNA vaccine Other Dzherelo

Restoring effectiveness of drugs by disrupting bacteriostatic pathways/fibrosis Thalidomide analogs Inhibit TNFα which is essential for granuloma formation Entanercept (soluble TNF receptor) High dose prednisone Concerns Requires concomitant bactericidal therapy Agents inhibit protective immunity thereby facilitating growth of organisms immunosuppression may result in OIs

Supplementing effector cytokines to assist with antimicrobial activity Rh-IFN-γ & α Rh-IL-2 Rh-GM-CSF IL-12

Latent TB infection Preventing HIV associated TB TB disease Restore / boost protective immunity ART Pre/Post exposure TB vaccines Treatment of latent TB infection Isoniazid preventive therapy

Isoniazid preventive therapy Good safety profile Effective, cheap & readily available? Public health benefit BUT Requires a long treatment period TB rates remain high in pts with advanced HIV disease Limited durability Adherence problematic Concern about promoting resistance

Increased side effects resulting in discontinuation Multi-drug TB preventive therapy regimens Efficacy compared to INH TB incidence rate ratio (RR) INH (13) RR = 0.67 INH + RIF (2) RR = 0.41 RIF + PZA (4) RR = 0.54 INH, RIF + PZA (1) RR = 0.48

LTBI with MDR\XDR TB MDR TB increased globally Close contacts of MDR/XDR TB patients are at increased risk of becoming infected PLHIV infected with MDR/XDR TB are at high risk of progressing to disease Almost no data and inconsistent international guidelines for treating contacts of MDR TB patients

HIV associated MDR & XDR TB in SA (N Gandhi, Am J Resp Crit Care Med, 2009)

Treatment of LTBI Effective, tolerable, ultra short course treatment for DS LTBI required Mouse model of LTBI (Eric Nuermberger) J>R>RH J=P=HP JP>PZ Effective treatment for LTBI with MDR/XDR TB urgently needed need to evaluate regimens in mouse model

1000.0 ELIMINATING TB BY 2050 Eliminating TB by 2050 BY PREVENTING INFECTION AND TREATING LATENT INFECTION Requires both PT and vaccines New TB cases/ million in 2050 100.0 10.0 1.0 0.1 0 0.03 Treatment 0.06 0.09 rate/latent/yr 0.09 0.06 0 0.03 Vaccinations/ uninfected/ yr

Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L) Control Group 0,5mm 4 lesions 1mm 3 lesions 2mm 1 lesion 0,5mm 7 lesions 1mm 4 lesions 11 Q 8 P L 34 0,5mm 3 lesions 1mm 25 lesions 2mm 6 lesions 29 0,5mm 18 lesions 1mm 8 lesions 2mm 3 lesions M M 0,5mm 1mm 2mm >2 Coalescent 0,5mm 24 lesions 1mm 75 lesions 2mm 10 lesions >2 2 (3mm) lesions Coalescent 1 (4mm) lesions 112 R 8 O 0,5mm 4 lesions 1mm 1 lesions 2mm 3 lesions N 69 0,5mm 53 lesions 1mm 13 lesions 2mm 3 lesions (Gill O. PLoS ONE 5(4): e10030. doi:10.1371/journal.pone.0010030) Qx Group 1 1mm 1 lesion 54 0,5mm 8 lesions 1mm 38 lesions 2mm 2 lesions >2 3 (3mm) 1 (5mm) 1(6mm) lesions Coalescent 1 (5mm) lesion R Q Left Lung Right Lung 1 0,5mm 1 lesion P L 10 0,5mm 5 lesions 1mm 4 lesions M 2mm 1 lesion 1 11 O N 0,5mm 5 lesions 1mm 5 lesions 2mm 1 lesion 0,5mm 1 lesion INH x 4weeks reduced # granuloma Reduced dissemination of infection Retarded evolution of granuloma Did not induce TB specific immunity Left Lung Right Lung RUTI Group 1 >2mm 1 (3mm) lesion Q 35 0,5mm 6 lesions 1mm 20 lesions R 2mm 8 lesions >2 2 (3mm) 1 (4mm) lesions P O L 1 0,5mm 1 lesion 6 0,5mm 3 lesions 1mm 3 lesions M 3 N 0,5mm 1 lesion 1mm 2 lesions INH x 4wks + RUTI x 2 reduced # granuloma Reduced dissemination of infection Promoted evolution of granuloma Induced TB specific immunity Left Lung Right Lung

Conclusion HIV associated TB accounts for the vast majority of TB in sub-saharan Africa Need new safe, short, effective regimens for HIV associated TB, including M/XDR TB Use of adjunctive immunotherapy should be evaluated Need new safe, short, effective regimens for treating LTBI, particularly for DR TB Therapeutic TB vaccines required

Acknowledgements Helen McIlleron Ann Ginsburg