issues in tb drug development: tb/hiv · sa has one of the worst tb epidemics in the world! •...
TRANSCRIPT
Issues in TB Drug DevelopmentTBHIV
Open Forum
Gavin Churchyard18th August 2010
Presentation outlinebull TBHIV
ndash Epidemiology ndash clinical aspects
bull HIV associated TBndash Drug-Drug interactionsndash Immunotherapy
bull Latent TB infectionndash New drugsndash TB vaccines
bull Conclusion
more people living with HIV
dying of TBNO
SA has one of the worst TB epidemics in the world
bull Ranked 5th globallybull 4th greatest number of MDR TB patientsbull Most number of HIV positive TB patients in
the worldndash 70 of TB cases HIV
co-infectedbull XDR TB
ndash Largely HIV associatedndash Very high mortality
Integrated TB and HIV treatment saves lives
bull SAPIT trialndash Integrated TB amp HIV treatment reduced mortality by
56 in HIV-infected TB patients with CD4 countslt500 cellsml3
bull CAMELIA trialndash 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 ARTP
erso
n-ye
ars
on p
rote
ase
inhi
bito
rs
Data courtesy of Drs D Ripin and M OrsquoBrien (CSHOR) Clinton Health Access Initiative [ 05012010]
ADULTS - failed 1st line ART
Infants and young children- 1st line
0
20000
40000
60000
80000
100000
120000
140000
160000
180000
200000
2009 2010 2011 2012 2013 2014
Argentina Botswana Brazil Cameroon China Cote dIvoire Ethiopia India Kenya Malawi Mexico Mozambique Namibia Nigeria Rwanda South Africa Tanzania Thailand Uganda Zambia Zimbabwe GLOBAL TOTAL10
Reference
PPD+
PPD-
PPD-unknown
Overall
TB
Relative Risk (Fixed) amp 95 CI
038
083
081
095
Death
08
102
084
10 10
064
Efficacy of TB preventive therapy among HIV-infected individuals
Woldehanna 2004 Cochrane review
Effect of IPT and ART on TB incidence and mortality
Golub AIDS2008 Incidence 100py aHR (95 CI)
No IPTART 71 1
ART 46 036 (025-05)
ARTIPT 11 011 (002-08)
Innes CROI 2010 Mortality100py aHR (95 CI)
ART 111 1
ARTIPT 35 047 (03-07)
Effect of IPT and ART on TB incidence and mortality
Golub AIDS2008 Incidence 100py aHR (95 CI)
No IPTART 71 1
ART 46 036 (025-05)
ARTIPT 11 011 (002-08)
Innes CROI 2010 Mortality100py aHR (95 CI)
ART 111 1
ARTIPT 35 047 (03-07)
Author Location Intentionto treat
PerProtocol
Martinson Soweto 19 69
Samandari BotswanaAll 54 65TST+ 93TST- 19
(Martinson et al Union conference 2008 CROI 2009)(Samandari et al Union Conference 2009)
Reduction in TB incidence with 36 vs 6 months IPT
Author Location Intentionto treat
PerProtocol
Martinson Soweto 19 69
Samandari BotswanaAll 54 65TST+ 93TST- 19
(Martinson et al Union conference 2008 CROI 2009)(Samandari et al Union Conference 2009)
Reduction in TB incidence with 36 vs 6 months IPT
New drugs amp regimens required for HIV associated TB
bull To increase ndash Efficacyndash Safety ndash tolerability
bull To decrease ndash treatment durationndash Complexityndash drug-drug interactions ndash cost
Rifapentine ndash food interactions
0
5
10
15
20
25
30
0 10 20 30 40 50 60
RFP
pla
sma
conc
(m
gL)
Time after dose (h)
0
2
4
6
8
10
12
14
0 10 20 30 40 50 60
25-D
RFP
pla
sma
conc
(m
gL)
Time after dose (h)
High fat meal
Bulk_Low fat meal
Bulk_High fat
Chicken soup
Fasted state
Zvada SP Antimicrob Agents Chemother 2010 54(8)3390-4
+86 (RSE=20)
Potential interactions bw fluroquinolones and antiretrovirals
bullSafety interactionsndash QT prolongation (LPVr)ndash Dysglycaemia (PIs)
bullPK interactionsndash chelation by multivalent anions (buffered ddI)ndash moxifloxacin is a UGT SGT substrate
Antimicrob Agents Chemother 2007 512861ndash6 and 2008 524037-42 J Antimicrob Chemother 2007 601398-401 Clin Infect Dis 2007 451001ndash7 J Int AIDS Soc 2008 11 S95 (abstr) J Infect
2008 57 78-81
CYP2B6
CYP2C9CYP2C8
CYP2B9
CYP3A4CYP3A7
UGTs
GSTs
SULTs
PXR
APBL
PXR regulates drug-metabolizing enzymes
MRP2
OATP2
MDR1PHASE II
PHASE IEFFLUX
TRANSPORTERS
INFLUX
BASELINE ACTIVITYPXR expressionenzymes activityamp transporters
(Pharmacogenomics 2008 9 1695ndash1709 Drug Metab Dispos 2006 101756-63 amp 2007 351400-7)
OATP1B1
Rifampicin is a potent activator of PXR
CYP2B6
CYP2C9CYP2C8
CYP2B9
CYP3A4
UGTs
GSTs
SULTs
PXR-RXR
APBL
MRP2
OATP2
MDR1
Activating ligands trigger altered expression of multiple of enzymes and transporters with
compound effects on substrate concentrations
DRUG
RIF
OATP1B1
CYP3A7
J Pharmacol Exp Ther 2003 304 223-28
Drug InteractionsDiarylquinolines(TMC207)
bullCYP 3A4 SubstratebullNo PK interactions with HZbullPK studies with EFV NVP LPVr awaited
Ethylene Diamines (SQ-109)
CYP 2D6 CYP 2C19 substrate
Nitroimidazoles (PA-824 OPC-67683)
Not metabolized by or interfere with CYP enzymes
oxazolidinones (PNU-100480 Linezolid )
Mono Aminine Oxidase InhibitorsNot metabolized by or interfere with drug metabolizing enzymes
Drug-Drug Interactions
(Source H McIlleron)
Combined toxicities
Example of Linezolidbull CNS toxicity EFVbull Peripheral neuropathy DDI D4Tbull Lactic acidosis D4Tbull Myelosuppression ZDV
(Source H McIlleron)
Role of adjunctive immunotherapy
bull Shortening the duration of TB treatment bull Improve treatment success of M(X)DR TBbull Reduce clinical complicationsbull Reduce rate of recurrent TB
Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
GMP manufacturing capacity existsIvIgHE2000 M vaccaeanti-IL-4 RUTI
GMP capacity to be establishedhsp65 DNA vaccine
OtherDzherelo
Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
GMP manufacturing capacity existsIvIgHE2000 M vaccaeanti-IL-4 RUTI
GMP capacity to be establishedhsp65 DNA vaccine
OtherDzherelo
bull Thalidomide analogsndash Inhibit TNFα which is essential for granuloma
formationbull Entanercept (soluble TNF receptor)bull High dose prednisone
Concernsbull Requires concomitant bactericidal therapybull Agents inhibit protective immunity thereby
facilitating growth of organismsbull immunosuppression may result in OIs
Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
Supplementing effector cytokines to assist with antimicrobial activityRh-IFN-γ amp αRh-IL-2Rh-GM-CSFIL-12
Preventing HIV associated TB
Latent TB infection
TB disease
Treatment of latent TB infection
bull Isoniazid preventive therapy
Restore boost protective immunitybull ARTbull PrePost exposure TB vaccines
Isoniazid preventive therapy
bull Good safety profilebull Effective cheap amp readily availablebull Public health benefitBUTbull Requires a long treatment periodbull TB rates remain high in pts with advanced
HIV diseasebull Limited durabilitybull Adherence problematicbull Concern about promoting resistance
bull Efficacy compared to INH
TB incidence rate ratio (RR)minus INH (13) RR = 067minus INH + RIF (2) RR = 041minus RIF + PZA (4) RR = 054minus INH RIF + PZA (1) RR = 048
bull Increased side effects resulting in discontinuation
Multi-drug TB preventive therapyregimens
LTBI with MDRXDR TB
bull MDR TB increased globallybull Close contacts of MDRXDR TB patients are
at increased risk of becoming infectedbull PLHIV infected with MDRXDR TB are at
high risk of progressing to diseasebull Almost no data and inconsistent
international guidelines for treating contacts of MDR TB patients
HIV associated MDR amp XDR TB in SA
(N Gandhi Am J Resp Crit Care Med 2009)
Treatment of LTBIbull Effective tolerable ultra short course
treatment for DS LTBI requiredndash Mouse model of LTBI
(Eric Nuermberger) bull JgtRgtRHbull J=P=HPbull JPgtPZ
bull Effective treatment for LTBI with MDRXDR TB urgently neededndash need to evaluate regimens in mouse model
0003
006009
0003
006009
01
10
100
1000
10000
New TB cases
million in 2050
Treatment ratelatentyr
Vaccinations uninfected yr
ELIMINATING TB BY 2050BY PREVENTING INFECTION AND TREATING LATENT
INFECTIONEliminating TB by 2050Requires both PT and vaccines
M
8
L
O
Q
P
Control Group05mm 3 lesions1mm 25 lesions2mm 6 lesions
05mm 18 lesions1mm 8 lesions2mm 3 lesions
05mm 53 lesions1mm 13 lesions2mm 3 lesions
05mm 4 lesions1mm 1 lesions2mm 3 lesions
05mm 4 lesions1mm 3 lesions2mm 1 lesion
05mm 7 lesions1mm 4 lesions
05mm 24 lesions1mm 75 lesions2mm 10 lesionsgt2 2 (3mm) lesionsCoalescent 1 (4mm)
lesions R
Left Lung Right Lung
11
112
869
29
34
N
M
L
NO
Q
Qx Group05mm 1 lesion
05mm 5 lesions1mm 4 lesions2mm 1 lesion
05mm 5 lesions1mm 5 lesions2mm 1 lesion
05mm 1 lesion
1mm 1 lesion
05mm 8 lesions1mm 38 lesions2mm 2 lesionsgt2 3 (3mm) 1 (5mm)
1(6mm) lesionsCoalescent 1 (5mm) lesion
M
P
Left Lung Right Lung
1
54
1
11
10
1
R
L
NOR
Q
P
RUTI Group05mm 1 lesion
05mm 3 lesions1mm 3 lesions
05mm 1 lesion1mm 2 lesions
gt2mm 1 (3mm) lesion
05mm 6 lesions1mm 20 lesions2mm 8 lesionsgt2 2 (3mm) 1 (4mm)
lesions
M
Left Lung Right Lung
35 3
6
11
05mm 1mm 2mm gt2 Coalescent
Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
INH x 4weeksbull reduced granulomabull Reduced dissemination of infectionbull Retarded evolution of granulomabullDid not induce TB specific immunity
INH x 4wks + RUTI x 2bull reduced granulomabullReduced dissemination of infectionbull Promoted evolution of granulomabull Induced TB specific immunity
(Gill O PLoS ONE 5(4) e10030 doi101371journalpone0010030)
Conclusion
bull HIV associated TB accounts for the vast majority of TB in sub-Saharan Africa
bull Need new safe short effective regimens for HIV associated TB including MXDR TB
bull Use of adjunctive immunotherapy should be evaluated
bull Need new safe short effective regimens for treating LTBI particularly for DR TB
bull Therapeutic TB vaccines required
Acknowledgements
bull Helen McIlleronbull Ann Ginsburg
- Issues in TB Drug DevelopmentTBHIV
- Presentation outline
- SA has one of the worst TB epidemics in the world
- Integrated TB and HIV treatment saves lives
- Projected use of PI-based ART
- Slide Number 6
- Effect of IPT and ART on TB incidence and mortality
- Effect of IPT and ART on TB incidence and mortality
- Reduction in TB incidence with 36 vs 6 months IPT
- Reduction in TB incidence with 36 vs 6 months IPT
- New drugs amp regimens required for HIV associated TB
- Rifapentine ndash food interactions
- Potential interactions bw fluroquinolones and antiretrovirals
- PXR regulates drug-metabolizing enzymes
- Rifampicin is a potent activator of PXR
- Drug-Drug Interactions
- Combined toxicities
- Role of adjunctive immunotherapy
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
- Supplementing effector cytokines to assist with antimicrobial activity
- Preventing HIV associated TB
- Isoniazid preventive therapy
- Slide Number 25
- LTBI with MDRXDR TB
- Slide Number 27
- Treatment of LTBI
- Slide Number 29
- Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
- Conclusion
- Acknowledgements
-
Presentation outlinebull TBHIV
ndash Epidemiology ndash clinical aspects
bull HIV associated TBndash Drug-Drug interactionsndash Immunotherapy
bull Latent TB infectionndash New drugsndash TB vaccines
bull Conclusion
more people living with HIV
dying of TBNO
SA has one of the worst TB epidemics in the world
bull Ranked 5th globallybull 4th greatest number of MDR TB patientsbull Most number of HIV positive TB patients in
the worldndash 70 of TB cases HIV
co-infectedbull XDR TB
ndash Largely HIV associatedndash Very high mortality
Integrated TB and HIV treatment saves lives
bull SAPIT trialndash Integrated TB amp HIV treatment reduced mortality by
56 in HIV-infected TB patients with CD4 countslt500 cellsml3
bull CAMELIA trialndash 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 ARTP
erso
n-ye
ars
on p
rote
ase
inhi
bito
rs
Data courtesy of Drs D Ripin and M OrsquoBrien (CSHOR) Clinton Health Access Initiative [ 05012010]
ADULTS - failed 1st line ART
Infants and young children- 1st line
0
20000
40000
60000
80000
100000
120000
140000
160000
180000
200000
2009 2010 2011 2012 2013 2014
Argentina Botswana Brazil Cameroon China Cote dIvoire Ethiopia India Kenya Malawi Mexico Mozambique Namibia Nigeria Rwanda South Africa Tanzania Thailand Uganda Zambia Zimbabwe GLOBAL TOTAL10
Reference
PPD+
PPD-
PPD-unknown
Overall
TB
Relative Risk (Fixed) amp 95 CI
038
083
081
095
Death
08
102
084
10 10
064
Efficacy of TB preventive therapy among HIV-infected individuals
Woldehanna 2004 Cochrane review
Effect of IPT and ART on TB incidence and mortality
Golub AIDS2008 Incidence 100py aHR (95 CI)
No IPTART 71 1
ART 46 036 (025-05)
ARTIPT 11 011 (002-08)
Innes CROI 2010 Mortality100py aHR (95 CI)
ART 111 1
ARTIPT 35 047 (03-07)
Effect of IPT and ART on TB incidence and mortality
Golub AIDS2008 Incidence 100py aHR (95 CI)
No IPTART 71 1
ART 46 036 (025-05)
ARTIPT 11 011 (002-08)
Innes CROI 2010 Mortality100py aHR (95 CI)
ART 111 1
ARTIPT 35 047 (03-07)
Author Location Intentionto treat
PerProtocol
Martinson Soweto 19 69
Samandari BotswanaAll 54 65TST+ 93TST- 19
(Martinson et al Union conference 2008 CROI 2009)(Samandari et al Union Conference 2009)
Reduction in TB incidence with 36 vs 6 months IPT
Author Location Intentionto treat
PerProtocol
Martinson Soweto 19 69
Samandari BotswanaAll 54 65TST+ 93TST- 19
(Martinson et al Union conference 2008 CROI 2009)(Samandari et al Union Conference 2009)
Reduction in TB incidence with 36 vs 6 months IPT
New drugs amp regimens required for HIV associated TB
bull To increase ndash Efficacyndash Safety ndash tolerability
bull To decrease ndash treatment durationndash Complexityndash drug-drug interactions ndash cost
Rifapentine ndash food interactions
0
5
10
15
20
25
30
0 10 20 30 40 50 60
RFP
pla
sma
conc
(m
gL)
Time after dose (h)
0
2
4
6
8
10
12
14
0 10 20 30 40 50 60
25-D
RFP
pla
sma
conc
(m
gL)
Time after dose (h)
High fat meal
Bulk_Low fat meal
Bulk_High fat
Chicken soup
Fasted state
Zvada SP Antimicrob Agents Chemother 2010 54(8)3390-4
+86 (RSE=20)
Potential interactions bw fluroquinolones and antiretrovirals
bullSafety interactionsndash QT prolongation (LPVr)ndash Dysglycaemia (PIs)
bullPK interactionsndash chelation by multivalent anions (buffered ddI)ndash moxifloxacin is a UGT SGT substrate
Antimicrob Agents Chemother 2007 512861ndash6 and 2008 524037-42 J Antimicrob Chemother 2007 601398-401 Clin Infect Dis 2007 451001ndash7 J Int AIDS Soc 2008 11 S95 (abstr) J Infect
2008 57 78-81
CYP2B6
CYP2C9CYP2C8
CYP2B9
CYP3A4CYP3A7
UGTs
GSTs
SULTs
PXR
APBL
PXR regulates drug-metabolizing enzymes
MRP2
OATP2
MDR1PHASE II
PHASE IEFFLUX
TRANSPORTERS
INFLUX
BASELINE ACTIVITYPXR expressionenzymes activityamp transporters
(Pharmacogenomics 2008 9 1695ndash1709 Drug Metab Dispos 2006 101756-63 amp 2007 351400-7)
OATP1B1
Rifampicin is a potent activator of PXR
CYP2B6
CYP2C9CYP2C8
CYP2B9
CYP3A4
UGTs
GSTs
SULTs
PXR-RXR
APBL
MRP2
OATP2
MDR1
Activating ligands trigger altered expression of multiple of enzymes and transporters with
compound effects on substrate concentrations
DRUG
RIF
OATP1B1
CYP3A7
J Pharmacol Exp Ther 2003 304 223-28
Drug InteractionsDiarylquinolines(TMC207)
bullCYP 3A4 SubstratebullNo PK interactions with HZbullPK studies with EFV NVP LPVr awaited
Ethylene Diamines (SQ-109)
CYP 2D6 CYP 2C19 substrate
Nitroimidazoles (PA-824 OPC-67683)
Not metabolized by or interfere with CYP enzymes
oxazolidinones (PNU-100480 Linezolid )
Mono Aminine Oxidase InhibitorsNot metabolized by or interfere with drug metabolizing enzymes
Drug-Drug Interactions
(Source H McIlleron)
Combined toxicities
Example of Linezolidbull CNS toxicity EFVbull Peripheral neuropathy DDI D4Tbull Lactic acidosis D4Tbull Myelosuppression ZDV
(Source H McIlleron)
Role of adjunctive immunotherapy
bull Shortening the duration of TB treatment bull Improve treatment success of M(X)DR TBbull Reduce clinical complicationsbull Reduce rate of recurrent TB
Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
GMP manufacturing capacity existsIvIgHE2000 M vaccaeanti-IL-4 RUTI
GMP capacity to be establishedhsp65 DNA vaccine
OtherDzherelo
Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
GMP manufacturing capacity existsIvIgHE2000 M vaccaeanti-IL-4 RUTI
GMP capacity to be establishedhsp65 DNA vaccine
OtherDzherelo
bull Thalidomide analogsndash Inhibit TNFα which is essential for granuloma
formationbull Entanercept (soluble TNF receptor)bull High dose prednisone
Concernsbull Requires concomitant bactericidal therapybull Agents inhibit protective immunity thereby
facilitating growth of organismsbull immunosuppression may result in OIs
Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
Supplementing effector cytokines to assist with antimicrobial activityRh-IFN-γ amp αRh-IL-2Rh-GM-CSFIL-12
Preventing HIV associated TB
Latent TB infection
TB disease
Treatment of latent TB infection
bull Isoniazid preventive therapy
Restore boost protective immunitybull ARTbull PrePost exposure TB vaccines
Isoniazid preventive therapy
bull Good safety profilebull Effective cheap amp readily availablebull Public health benefitBUTbull Requires a long treatment periodbull TB rates remain high in pts with advanced
HIV diseasebull Limited durabilitybull Adherence problematicbull Concern about promoting resistance
bull Efficacy compared to INH
TB incidence rate ratio (RR)minus INH (13) RR = 067minus INH + RIF (2) RR = 041minus RIF + PZA (4) RR = 054minus INH RIF + PZA (1) RR = 048
bull Increased side effects resulting in discontinuation
Multi-drug TB preventive therapyregimens
LTBI with MDRXDR TB
bull MDR TB increased globallybull Close contacts of MDRXDR TB patients are
at increased risk of becoming infectedbull PLHIV infected with MDRXDR TB are at
high risk of progressing to diseasebull Almost no data and inconsistent
international guidelines for treating contacts of MDR TB patients
HIV associated MDR amp XDR TB in SA
(N Gandhi Am J Resp Crit Care Med 2009)
Treatment of LTBIbull Effective tolerable ultra short course
treatment for DS LTBI requiredndash Mouse model of LTBI
(Eric Nuermberger) bull JgtRgtRHbull J=P=HPbull JPgtPZ
bull Effective treatment for LTBI with MDRXDR TB urgently neededndash need to evaluate regimens in mouse model
0003
006009
0003
006009
01
10
100
1000
10000
New TB cases
million in 2050
Treatment ratelatentyr
Vaccinations uninfected yr
ELIMINATING TB BY 2050BY PREVENTING INFECTION AND TREATING LATENT
INFECTIONEliminating TB by 2050Requires both PT and vaccines
M
8
L
O
Q
P
Control Group05mm 3 lesions1mm 25 lesions2mm 6 lesions
05mm 18 lesions1mm 8 lesions2mm 3 lesions
05mm 53 lesions1mm 13 lesions2mm 3 lesions
05mm 4 lesions1mm 1 lesions2mm 3 lesions
05mm 4 lesions1mm 3 lesions2mm 1 lesion
05mm 7 lesions1mm 4 lesions
05mm 24 lesions1mm 75 lesions2mm 10 lesionsgt2 2 (3mm) lesionsCoalescent 1 (4mm)
lesions R
Left Lung Right Lung
11
112
869
29
34
N
M
L
NO
Q
Qx Group05mm 1 lesion
05mm 5 lesions1mm 4 lesions2mm 1 lesion
05mm 5 lesions1mm 5 lesions2mm 1 lesion
05mm 1 lesion
1mm 1 lesion
05mm 8 lesions1mm 38 lesions2mm 2 lesionsgt2 3 (3mm) 1 (5mm)
1(6mm) lesionsCoalescent 1 (5mm) lesion
M
P
Left Lung Right Lung
1
54
1
11
10
1
R
L
NOR
Q
P
RUTI Group05mm 1 lesion
05mm 3 lesions1mm 3 lesions
05mm 1 lesion1mm 2 lesions
gt2mm 1 (3mm) lesion
05mm 6 lesions1mm 20 lesions2mm 8 lesionsgt2 2 (3mm) 1 (4mm)
lesions
M
Left Lung Right Lung
35 3
6
11
05mm 1mm 2mm gt2 Coalescent
Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
INH x 4weeksbull reduced granulomabull Reduced dissemination of infectionbull Retarded evolution of granulomabullDid not induce TB specific immunity
INH x 4wks + RUTI x 2bull reduced granulomabullReduced dissemination of infectionbull Promoted evolution of granulomabull Induced TB specific immunity
(Gill O PLoS ONE 5(4) e10030 doi101371journalpone0010030)
Conclusion
bull HIV associated TB accounts for the vast majority of TB in sub-Saharan Africa
bull Need new safe short effective regimens for HIV associated TB including MXDR TB
bull Use of adjunctive immunotherapy should be evaluated
bull Need new safe short effective regimens for treating LTBI particularly for DR TB
bull Therapeutic TB vaccines required
Acknowledgements
bull Helen McIlleronbull Ann Ginsburg
- Issues in TB Drug DevelopmentTBHIV
- Presentation outline
- SA has one of the worst TB epidemics in the world
- Integrated TB and HIV treatment saves lives
- Projected use of PI-based ART
- Slide Number 6
- Effect of IPT and ART on TB incidence and mortality
- Effect of IPT and ART on TB incidence and mortality
- Reduction in TB incidence with 36 vs 6 months IPT
- Reduction in TB incidence with 36 vs 6 months IPT
- New drugs amp regimens required for HIV associated TB
- Rifapentine ndash food interactions
- Potential interactions bw fluroquinolones and antiretrovirals
- PXR regulates drug-metabolizing enzymes
- Rifampicin is a potent activator of PXR
- Drug-Drug Interactions
- Combined toxicities
- Role of adjunctive immunotherapy
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
- Supplementing effector cytokines to assist with antimicrobial activity
- Preventing HIV associated TB
- Isoniazid preventive therapy
- Slide Number 25
- LTBI with MDRXDR TB
- Slide Number 27
- Treatment of LTBI
- Slide Number 29
- Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
- Conclusion
- Acknowledgements
-
SA has one of the worst TB epidemics in the world
bull Ranked 5th globallybull 4th greatest number of MDR TB patientsbull Most number of HIV positive TB patients in
the worldndash 70 of TB cases HIV
co-infectedbull XDR TB
ndash Largely HIV associatedndash Very high mortality
Integrated TB and HIV treatment saves lives
bull SAPIT trialndash Integrated TB amp HIV treatment reduced mortality by
56 in HIV-infected TB patients with CD4 countslt500 cellsml3
bull CAMELIA trialndash 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 ARTP
erso
n-ye
ars
on p
rote
ase
inhi
bito
rs
Data courtesy of Drs D Ripin and M OrsquoBrien (CSHOR) Clinton Health Access Initiative [ 05012010]
ADULTS - failed 1st line ART
Infants and young children- 1st line
0
20000
40000
60000
80000
100000
120000
140000
160000
180000
200000
2009 2010 2011 2012 2013 2014
Argentina Botswana Brazil Cameroon China Cote dIvoire Ethiopia India Kenya Malawi Mexico Mozambique Namibia Nigeria Rwanda South Africa Tanzania Thailand Uganda Zambia Zimbabwe GLOBAL TOTAL10
Reference
PPD+
PPD-
PPD-unknown
Overall
TB
Relative Risk (Fixed) amp 95 CI
038
083
081
095
Death
08
102
084
10 10
064
Efficacy of TB preventive therapy among HIV-infected individuals
Woldehanna 2004 Cochrane review
Effect of IPT and ART on TB incidence and mortality
Golub AIDS2008 Incidence 100py aHR (95 CI)
No IPTART 71 1
ART 46 036 (025-05)
ARTIPT 11 011 (002-08)
Innes CROI 2010 Mortality100py aHR (95 CI)
ART 111 1
ARTIPT 35 047 (03-07)
Effect of IPT and ART on TB incidence and mortality
Golub AIDS2008 Incidence 100py aHR (95 CI)
No IPTART 71 1
ART 46 036 (025-05)
ARTIPT 11 011 (002-08)
Innes CROI 2010 Mortality100py aHR (95 CI)
ART 111 1
ARTIPT 35 047 (03-07)
Author Location Intentionto treat
PerProtocol
Martinson Soweto 19 69
Samandari BotswanaAll 54 65TST+ 93TST- 19
(Martinson et al Union conference 2008 CROI 2009)(Samandari et al Union Conference 2009)
Reduction in TB incidence with 36 vs 6 months IPT
Author Location Intentionto treat
PerProtocol
Martinson Soweto 19 69
Samandari BotswanaAll 54 65TST+ 93TST- 19
(Martinson et al Union conference 2008 CROI 2009)(Samandari et al Union Conference 2009)
Reduction in TB incidence with 36 vs 6 months IPT
New drugs amp regimens required for HIV associated TB
bull To increase ndash Efficacyndash Safety ndash tolerability
bull To decrease ndash treatment durationndash Complexityndash drug-drug interactions ndash cost
Rifapentine ndash food interactions
0
5
10
15
20
25
30
0 10 20 30 40 50 60
RFP
pla
sma
conc
(m
gL)
Time after dose (h)
0
2
4
6
8
10
12
14
0 10 20 30 40 50 60
25-D
RFP
pla
sma
conc
(m
gL)
Time after dose (h)
High fat meal
Bulk_Low fat meal
Bulk_High fat
Chicken soup
Fasted state
Zvada SP Antimicrob Agents Chemother 2010 54(8)3390-4
+86 (RSE=20)
Potential interactions bw fluroquinolones and antiretrovirals
bullSafety interactionsndash QT prolongation (LPVr)ndash Dysglycaemia (PIs)
bullPK interactionsndash chelation by multivalent anions (buffered ddI)ndash moxifloxacin is a UGT SGT substrate
Antimicrob Agents Chemother 2007 512861ndash6 and 2008 524037-42 J Antimicrob Chemother 2007 601398-401 Clin Infect Dis 2007 451001ndash7 J Int AIDS Soc 2008 11 S95 (abstr) J Infect
2008 57 78-81
CYP2B6
CYP2C9CYP2C8
CYP2B9
CYP3A4CYP3A7
UGTs
GSTs
SULTs
PXR
APBL
PXR regulates drug-metabolizing enzymes
MRP2
OATP2
MDR1PHASE II
PHASE IEFFLUX
TRANSPORTERS
INFLUX
BASELINE ACTIVITYPXR expressionenzymes activityamp transporters
(Pharmacogenomics 2008 9 1695ndash1709 Drug Metab Dispos 2006 101756-63 amp 2007 351400-7)
OATP1B1
Rifampicin is a potent activator of PXR
CYP2B6
CYP2C9CYP2C8
CYP2B9
CYP3A4
UGTs
GSTs
SULTs
PXR-RXR
APBL
MRP2
OATP2
MDR1
Activating ligands trigger altered expression of multiple of enzymes and transporters with
compound effects on substrate concentrations
DRUG
RIF
OATP1B1
CYP3A7
J Pharmacol Exp Ther 2003 304 223-28
Drug InteractionsDiarylquinolines(TMC207)
bullCYP 3A4 SubstratebullNo PK interactions with HZbullPK studies with EFV NVP LPVr awaited
Ethylene Diamines (SQ-109)
CYP 2D6 CYP 2C19 substrate
Nitroimidazoles (PA-824 OPC-67683)
Not metabolized by or interfere with CYP enzymes
oxazolidinones (PNU-100480 Linezolid )
Mono Aminine Oxidase InhibitorsNot metabolized by or interfere with drug metabolizing enzymes
Drug-Drug Interactions
(Source H McIlleron)
Combined toxicities
Example of Linezolidbull CNS toxicity EFVbull Peripheral neuropathy DDI D4Tbull Lactic acidosis D4Tbull Myelosuppression ZDV
(Source H McIlleron)
Role of adjunctive immunotherapy
bull Shortening the duration of TB treatment bull Improve treatment success of M(X)DR TBbull Reduce clinical complicationsbull Reduce rate of recurrent TB
Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
GMP manufacturing capacity existsIvIgHE2000 M vaccaeanti-IL-4 RUTI
GMP capacity to be establishedhsp65 DNA vaccine
OtherDzherelo
Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
GMP manufacturing capacity existsIvIgHE2000 M vaccaeanti-IL-4 RUTI
GMP capacity to be establishedhsp65 DNA vaccine
OtherDzherelo
bull Thalidomide analogsndash Inhibit TNFα which is essential for granuloma
formationbull Entanercept (soluble TNF receptor)bull High dose prednisone
Concernsbull Requires concomitant bactericidal therapybull Agents inhibit protective immunity thereby
facilitating growth of organismsbull immunosuppression may result in OIs
Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
Supplementing effector cytokines to assist with antimicrobial activityRh-IFN-γ amp αRh-IL-2Rh-GM-CSFIL-12
Preventing HIV associated TB
Latent TB infection
TB disease
Treatment of latent TB infection
bull Isoniazid preventive therapy
Restore boost protective immunitybull ARTbull PrePost exposure TB vaccines
Isoniazid preventive therapy
bull Good safety profilebull Effective cheap amp readily availablebull Public health benefitBUTbull Requires a long treatment periodbull TB rates remain high in pts with advanced
HIV diseasebull Limited durabilitybull Adherence problematicbull Concern about promoting resistance
bull Efficacy compared to INH
TB incidence rate ratio (RR)minus INH (13) RR = 067minus INH + RIF (2) RR = 041minus RIF + PZA (4) RR = 054minus INH RIF + PZA (1) RR = 048
bull Increased side effects resulting in discontinuation
Multi-drug TB preventive therapyregimens
LTBI with MDRXDR TB
bull MDR TB increased globallybull Close contacts of MDRXDR TB patients are
at increased risk of becoming infectedbull PLHIV infected with MDRXDR TB are at
high risk of progressing to diseasebull Almost no data and inconsistent
international guidelines for treating contacts of MDR TB patients
HIV associated MDR amp XDR TB in SA
(N Gandhi Am J Resp Crit Care Med 2009)
Treatment of LTBIbull Effective tolerable ultra short course
treatment for DS LTBI requiredndash Mouse model of LTBI
(Eric Nuermberger) bull JgtRgtRHbull J=P=HPbull JPgtPZ
bull Effective treatment for LTBI with MDRXDR TB urgently neededndash need to evaluate regimens in mouse model
0003
006009
0003
006009
01
10
100
1000
10000
New TB cases
million in 2050
Treatment ratelatentyr
Vaccinations uninfected yr
ELIMINATING TB BY 2050BY PREVENTING INFECTION AND TREATING LATENT
INFECTIONEliminating TB by 2050Requires both PT and vaccines
M
8
L
O
Q
P
Control Group05mm 3 lesions1mm 25 lesions2mm 6 lesions
05mm 18 lesions1mm 8 lesions2mm 3 lesions
05mm 53 lesions1mm 13 lesions2mm 3 lesions
05mm 4 lesions1mm 1 lesions2mm 3 lesions
05mm 4 lesions1mm 3 lesions2mm 1 lesion
05mm 7 lesions1mm 4 lesions
05mm 24 lesions1mm 75 lesions2mm 10 lesionsgt2 2 (3mm) lesionsCoalescent 1 (4mm)
lesions R
Left Lung Right Lung
11
112
869
29
34
N
M
L
NO
Q
Qx Group05mm 1 lesion
05mm 5 lesions1mm 4 lesions2mm 1 lesion
05mm 5 lesions1mm 5 lesions2mm 1 lesion
05mm 1 lesion
1mm 1 lesion
05mm 8 lesions1mm 38 lesions2mm 2 lesionsgt2 3 (3mm) 1 (5mm)
1(6mm) lesionsCoalescent 1 (5mm) lesion
M
P
Left Lung Right Lung
1
54
1
11
10
1
R
L
NOR
Q
P
RUTI Group05mm 1 lesion
05mm 3 lesions1mm 3 lesions
05mm 1 lesion1mm 2 lesions
gt2mm 1 (3mm) lesion
05mm 6 lesions1mm 20 lesions2mm 8 lesionsgt2 2 (3mm) 1 (4mm)
lesions
M
Left Lung Right Lung
35 3
6
11
05mm 1mm 2mm gt2 Coalescent
Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
INH x 4weeksbull reduced granulomabull Reduced dissemination of infectionbull Retarded evolution of granulomabullDid not induce TB specific immunity
INH x 4wks + RUTI x 2bull reduced granulomabullReduced dissemination of infectionbull Promoted evolution of granulomabull Induced TB specific immunity
(Gill O PLoS ONE 5(4) e10030 doi101371journalpone0010030)
Conclusion
bull HIV associated TB accounts for the vast majority of TB in sub-Saharan Africa
bull Need new safe short effective regimens for HIV associated TB including MXDR TB
bull Use of adjunctive immunotherapy should be evaluated
bull Need new safe short effective regimens for treating LTBI particularly for DR TB
bull Therapeutic TB vaccines required
Acknowledgements
bull Helen McIlleronbull Ann Ginsburg
- Issues in TB Drug DevelopmentTBHIV
- Presentation outline
- SA has one of the worst TB epidemics in the world
- Integrated TB and HIV treatment saves lives
- Projected use of PI-based ART
- Slide Number 6
- Effect of IPT and ART on TB incidence and mortality
- Effect of IPT and ART on TB incidence and mortality
- Reduction in TB incidence with 36 vs 6 months IPT
- Reduction in TB incidence with 36 vs 6 months IPT
- New drugs amp regimens required for HIV associated TB
- Rifapentine ndash food interactions
- Potential interactions bw fluroquinolones and antiretrovirals
- PXR regulates drug-metabolizing enzymes
- Rifampicin is a potent activator of PXR
- Drug-Drug Interactions
- Combined toxicities
- Role of adjunctive immunotherapy
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
- Supplementing effector cytokines to assist with antimicrobial activity
- Preventing HIV associated TB
- Isoniazid preventive therapy
- Slide Number 25
- LTBI with MDRXDR TB
- Slide Number 27
- Treatment of LTBI
- Slide Number 29
- Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
- Conclusion
- Acknowledgements
-
Integrated TB and HIV treatment saves lives
bull SAPIT trialndash Integrated TB amp HIV treatment reduced mortality by
56 in HIV-infected TB patients with CD4 countslt500 cellsml3
bull CAMELIA trialndash 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 ARTP
erso
n-ye
ars
on p
rote
ase
inhi
bito
rs
Data courtesy of Drs D Ripin and M OrsquoBrien (CSHOR) Clinton Health Access Initiative [ 05012010]
ADULTS - failed 1st line ART
Infants and young children- 1st line
0
20000
40000
60000
80000
100000
120000
140000
160000
180000
200000
2009 2010 2011 2012 2013 2014
Argentina Botswana Brazil Cameroon China Cote dIvoire Ethiopia India Kenya Malawi Mexico Mozambique Namibia Nigeria Rwanda South Africa Tanzania Thailand Uganda Zambia Zimbabwe GLOBAL TOTAL10
Reference
PPD+
PPD-
PPD-unknown
Overall
TB
Relative Risk (Fixed) amp 95 CI
038
083
081
095
Death
08
102
084
10 10
064
Efficacy of TB preventive therapy among HIV-infected individuals
Woldehanna 2004 Cochrane review
Effect of IPT and ART on TB incidence and mortality
Golub AIDS2008 Incidence 100py aHR (95 CI)
No IPTART 71 1
ART 46 036 (025-05)
ARTIPT 11 011 (002-08)
Innes CROI 2010 Mortality100py aHR (95 CI)
ART 111 1
ARTIPT 35 047 (03-07)
Effect of IPT and ART on TB incidence and mortality
Golub AIDS2008 Incidence 100py aHR (95 CI)
No IPTART 71 1
ART 46 036 (025-05)
ARTIPT 11 011 (002-08)
Innes CROI 2010 Mortality100py aHR (95 CI)
ART 111 1
ARTIPT 35 047 (03-07)
Author Location Intentionto treat
PerProtocol
Martinson Soweto 19 69
Samandari BotswanaAll 54 65TST+ 93TST- 19
(Martinson et al Union conference 2008 CROI 2009)(Samandari et al Union Conference 2009)
Reduction in TB incidence with 36 vs 6 months IPT
Author Location Intentionto treat
PerProtocol
Martinson Soweto 19 69
Samandari BotswanaAll 54 65TST+ 93TST- 19
(Martinson et al Union conference 2008 CROI 2009)(Samandari et al Union Conference 2009)
Reduction in TB incidence with 36 vs 6 months IPT
New drugs amp regimens required for HIV associated TB
bull To increase ndash Efficacyndash Safety ndash tolerability
bull To decrease ndash treatment durationndash Complexityndash drug-drug interactions ndash cost
Rifapentine ndash food interactions
0
5
10
15
20
25
30
0 10 20 30 40 50 60
RFP
pla
sma
conc
(m
gL)
Time after dose (h)
0
2
4
6
8
10
12
14
0 10 20 30 40 50 60
25-D
RFP
pla
sma
conc
(m
gL)
Time after dose (h)
High fat meal
Bulk_Low fat meal
Bulk_High fat
Chicken soup
Fasted state
Zvada SP Antimicrob Agents Chemother 2010 54(8)3390-4
+86 (RSE=20)
Potential interactions bw fluroquinolones and antiretrovirals
bullSafety interactionsndash QT prolongation (LPVr)ndash Dysglycaemia (PIs)
bullPK interactionsndash chelation by multivalent anions (buffered ddI)ndash moxifloxacin is a UGT SGT substrate
Antimicrob Agents Chemother 2007 512861ndash6 and 2008 524037-42 J Antimicrob Chemother 2007 601398-401 Clin Infect Dis 2007 451001ndash7 J Int AIDS Soc 2008 11 S95 (abstr) J Infect
2008 57 78-81
CYP2B6
CYP2C9CYP2C8
CYP2B9
CYP3A4CYP3A7
UGTs
GSTs
SULTs
PXR
APBL
PXR regulates drug-metabolizing enzymes
MRP2
OATP2
MDR1PHASE II
PHASE IEFFLUX
TRANSPORTERS
INFLUX
BASELINE ACTIVITYPXR expressionenzymes activityamp transporters
(Pharmacogenomics 2008 9 1695ndash1709 Drug Metab Dispos 2006 101756-63 amp 2007 351400-7)
OATP1B1
Rifampicin is a potent activator of PXR
CYP2B6
CYP2C9CYP2C8
CYP2B9
CYP3A4
UGTs
GSTs
SULTs
PXR-RXR
APBL
MRP2
OATP2
MDR1
Activating ligands trigger altered expression of multiple of enzymes and transporters with
compound effects on substrate concentrations
DRUG
RIF
OATP1B1
CYP3A7
J Pharmacol Exp Ther 2003 304 223-28
Drug InteractionsDiarylquinolines(TMC207)
bullCYP 3A4 SubstratebullNo PK interactions with HZbullPK studies with EFV NVP LPVr awaited
Ethylene Diamines (SQ-109)
CYP 2D6 CYP 2C19 substrate
Nitroimidazoles (PA-824 OPC-67683)
Not metabolized by or interfere with CYP enzymes
oxazolidinones (PNU-100480 Linezolid )
Mono Aminine Oxidase InhibitorsNot metabolized by or interfere with drug metabolizing enzymes
Drug-Drug Interactions
(Source H McIlleron)
Combined toxicities
Example of Linezolidbull CNS toxicity EFVbull Peripheral neuropathy DDI D4Tbull Lactic acidosis D4Tbull Myelosuppression ZDV
(Source H McIlleron)
Role of adjunctive immunotherapy
bull Shortening the duration of TB treatment bull Improve treatment success of M(X)DR TBbull Reduce clinical complicationsbull Reduce rate of recurrent TB
Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
GMP manufacturing capacity existsIvIgHE2000 M vaccaeanti-IL-4 RUTI
GMP capacity to be establishedhsp65 DNA vaccine
OtherDzherelo
Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
GMP manufacturing capacity existsIvIgHE2000 M vaccaeanti-IL-4 RUTI
GMP capacity to be establishedhsp65 DNA vaccine
OtherDzherelo
bull Thalidomide analogsndash Inhibit TNFα which is essential for granuloma
formationbull Entanercept (soluble TNF receptor)bull High dose prednisone
Concernsbull Requires concomitant bactericidal therapybull Agents inhibit protective immunity thereby
facilitating growth of organismsbull immunosuppression may result in OIs
Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
Supplementing effector cytokines to assist with antimicrobial activityRh-IFN-γ amp αRh-IL-2Rh-GM-CSFIL-12
Preventing HIV associated TB
Latent TB infection
TB disease
Treatment of latent TB infection
bull Isoniazid preventive therapy
Restore boost protective immunitybull ARTbull PrePost exposure TB vaccines
Isoniazid preventive therapy
bull Good safety profilebull Effective cheap amp readily availablebull Public health benefitBUTbull Requires a long treatment periodbull TB rates remain high in pts with advanced
HIV diseasebull Limited durabilitybull Adherence problematicbull Concern about promoting resistance
bull Efficacy compared to INH
TB incidence rate ratio (RR)minus INH (13) RR = 067minus INH + RIF (2) RR = 041minus RIF + PZA (4) RR = 054minus INH RIF + PZA (1) RR = 048
bull Increased side effects resulting in discontinuation
Multi-drug TB preventive therapyregimens
LTBI with MDRXDR TB
bull MDR TB increased globallybull Close contacts of MDRXDR TB patients are
at increased risk of becoming infectedbull PLHIV infected with MDRXDR TB are at
high risk of progressing to diseasebull Almost no data and inconsistent
international guidelines for treating contacts of MDR TB patients
HIV associated MDR amp XDR TB in SA
(N Gandhi Am J Resp Crit Care Med 2009)
Treatment of LTBIbull Effective tolerable ultra short course
treatment for DS LTBI requiredndash Mouse model of LTBI
(Eric Nuermberger) bull JgtRgtRHbull J=P=HPbull JPgtPZ
bull Effective treatment for LTBI with MDRXDR TB urgently neededndash need to evaluate regimens in mouse model
0003
006009
0003
006009
01
10
100
1000
10000
New TB cases
million in 2050
Treatment ratelatentyr
Vaccinations uninfected yr
ELIMINATING TB BY 2050BY PREVENTING INFECTION AND TREATING LATENT
INFECTIONEliminating TB by 2050Requires both PT and vaccines
M
8
L
O
Q
P
Control Group05mm 3 lesions1mm 25 lesions2mm 6 lesions
05mm 18 lesions1mm 8 lesions2mm 3 lesions
05mm 53 lesions1mm 13 lesions2mm 3 lesions
05mm 4 lesions1mm 1 lesions2mm 3 lesions
05mm 4 lesions1mm 3 lesions2mm 1 lesion
05mm 7 lesions1mm 4 lesions
05mm 24 lesions1mm 75 lesions2mm 10 lesionsgt2 2 (3mm) lesionsCoalescent 1 (4mm)
lesions R
Left Lung Right Lung
11
112
869
29
34
N
M
L
NO
Q
Qx Group05mm 1 lesion
05mm 5 lesions1mm 4 lesions2mm 1 lesion
05mm 5 lesions1mm 5 lesions2mm 1 lesion
05mm 1 lesion
1mm 1 lesion
05mm 8 lesions1mm 38 lesions2mm 2 lesionsgt2 3 (3mm) 1 (5mm)
1(6mm) lesionsCoalescent 1 (5mm) lesion
M
P
Left Lung Right Lung
1
54
1
11
10
1
R
L
NOR
Q
P
RUTI Group05mm 1 lesion
05mm 3 lesions1mm 3 lesions
05mm 1 lesion1mm 2 lesions
gt2mm 1 (3mm) lesion
05mm 6 lesions1mm 20 lesions2mm 8 lesionsgt2 2 (3mm) 1 (4mm)
lesions
M
Left Lung Right Lung
35 3
6
11
05mm 1mm 2mm gt2 Coalescent
Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
INH x 4weeksbull reduced granulomabull Reduced dissemination of infectionbull Retarded evolution of granulomabullDid not induce TB specific immunity
INH x 4wks + RUTI x 2bull reduced granulomabullReduced dissemination of infectionbull Promoted evolution of granulomabull Induced TB specific immunity
(Gill O PLoS ONE 5(4) e10030 doi101371journalpone0010030)
Conclusion
bull HIV associated TB accounts for the vast majority of TB in sub-Saharan Africa
bull Need new safe short effective regimens for HIV associated TB including MXDR TB
bull Use of adjunctive immunotherapy should be evaluated
bull Need new safe short effective regimens for treating LTBI particularly for DR TB
bull Therapeutic TB vaccines required
Acknowledgements
bull Helen McIlleronbull Ann Ginsburg
- Issues in TB Drug DevelopmentTBHIV
- Presentation outline
- SA has one of the worst TB epidemics in the world
- Integrated TB and HIV treatment saves lives
- Projected use of PI-based ART
- Slide Number 6
- Effect of IPT and ART on TB incidence and mortality
- Effect of IPT and ART on TB incidence and mortality
- Reduction in TB incidence with 36 vs 6 months IPT
- Reduction in TB incidence with 36 vs 6 months IPT
- New drugs amp regimens required for HIV associated TB
- Rifapentine ndash food interactions
- Potential interactions bw fluroquinolones and antiretrovirals
- PXR regulates drug-metabolizing enzymes
- Rifampicin is a potent activator of PXR
- Drug-Drug Interactions
- Combined toxicities
- Role of adjunctive immunotherapy
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
- Supplementing effector cytokines to assist with antimicrobial activity
- Preventing HIV associated TB
- Isoniazid preventive therapy
- Slide Number 25
- LTBI with MDRXDR TB
- Slide Number 27
- Treatment of LTBI
- Slide Number 29
- Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
- Conclusion
- Acknowledgements
-
Projected use of PI-based ARTP
erso
n-ye
ars
on p
rote
ase
inhi
bito
rs
Data courtesy of Drs D Ripin and M OrsquoBrien (CSHOR) Clinton Health Access Initiative [ 05012010]
ADULTS - failed 1st line ART
Infants and young children- 1st line
0
20000
40000
60000
80000
100000
120000
140000
160000
180000
200000
2009 2010 2011 2012 2013 2014
Argentina Botswana Brazil Cameroon China Cote dIvoire Ethiopia India Kenya Malawi Mexico Mozambique Namibia Nigeria Rwanda South Africa Tanzania Thailand Uganda Zambia Zimbabwe GLOBAL TOTAL10
Reference
PPD+
PPD-
PPD-unknown
Overall
TB
Relative Risk (Fixed) amp 95 CI
038
083
081
095
Death
08
102
084
10 10
064
Efficacy of TB preventive therapy among HIV-infected individuals
Woldehanna 2004 Cochrane review
Effect of IPT and ART on TB incidence and mortality
Golub AIDS2008 Incidence 100py aHR (95 CI)
No IPTART 71 1
ART 46 036 (025-05)
ARTIPT 11 011 (002-08)
Innes CROI 2010 Mortality100py aHR (95 CI)
ART 111 1
ARTIPT 35 047 (03-07)
Effect of IPT and ART on TB incidence and mortality
Golub AIDS2008 Incidence 100py aHR (95 CI)
No IPTART 71 1
ART 46 036 (025-05)
ARTIPT 11 011 (002-08)
Innes CROI 2010 Mortality100py aHR (95 CI)
ART 111 1
ARTIPT 35 047 (03-07)
Author Location Intentionto treat
PerProtocol
Martinson Soweto 19 69
Samandari BotswanaAll 54 65TST+ 93TST- 19
(Martinson et al Union conference 2008 CROI 2009)(Samandari et al Union Conference 2009)
Reduction in TB incidence with 36 vs 6 months IPT
Author Location Intentionto treat
PerProtocol
Martinson Soweto 19 69
Samandari BotswanaAll 54 65TST+ 93TST- 19
(Martinson et al Union conference 2008 CROI 2009)(Samandari et al Union Conference 2009)
Reduction in TB incidence with 36 vs 6 months IPT
New drugs amp regimens required for HIV associated TB
bull To increase ndash Efficacyndash Safety ndash tolerability
bull To decrease ndash treatment durationndash Complexityndash drug-drug interactions ndash cost
Rifapentine ndash food interactions
0
5
10
15
20
25
30
0 10 20 30 40 50 60
RFP
pla
sma
conc
(m
gL)
Time after dose (h)
0
2
4
6
8
10
12
14
0 10 20 30 40 50 60
25-D
RFP
pla
sma
conc
(m
gL)
Time after dose (h)
High fat meal
Bulk_Low fat meal
Bulk_High fat
Chicken soup
Fasted state
Zvada SP Antimicrob Agents Chemother 2010 54(8)3390-4
+86 (RSE=20)
Potential interactions bw fluroquinolones and antiretrovirals
bullSafety interactionsndash QT prolongation (LPVr)ndash Dysglycaemia (PIs)
bullPK interactionsndash chelation by multivalent anions (buffered ddI)ndash moxifloxacin is a UGT SGT substrate
Antimicrob Agents Chemother 2007 512861ndash6 and 2008 524037-42 J Antimicrob Chemother 2007 601398-401 Clin Infect Dis 2007 451001ndash7 J Int AIDS Soc 2008 11 S95 (abstr) J Infect
2008 57 78-81
CYP2B6
CYP2C9CYP2C8
CYP2B9
CYP3A4CYP3A7
UGTs
GSTs
SULTs
PXR
APBL
PXR regulates drug-metabolizing enzymes
MRP2
OATP2
MDR1PHASE II
PHASE IEFFLUX
TRANSPORTERS
INFLUX
BASELINE ACTIVITYPXR expressionenzymes activityamp transporters
(Pharmacogenomics 2008 9 1695ndash1709 Drug Metab Dispos 2006 101756-63 amp 2007 351400-7)
OATP1B1
Rifampicin is a potent activator of PXR
CYP2B6
CYP2C9CYP2C8
CYP2B9
CYP3A4
UGTs
GSTs
SULTs
PXR-RXR
APBL
MRP2
OATP2
MDR1
Activating ligands trigger altered expression of multiple of enzymes and transporters with
compound effects on substrate concentrations
DRUG
RIF
OATP1B1
CYP3A7
J Pharmacol Exp Ther 2003 304 223-28
Drug InteractionsDiarylquinolines(TMC207)
bullCYP 3A4 SubstratebullNo PK interactions with HZbullPK studies with EFV NVP LPVr awaited
Ethylene Diamines (SQ-109)
CYP 2D6 CYP 2C19 substrate
Nitroimidazoles (PA-824 OPC-67683)
Not metabolized by or interfere with CYP enzymes
oxazolidinones (PNU-100480 Linezolid )
Mono Aminine Oxidase InhibitorsNot metabolized by or interfere with drug metabolizing enzymes
Drug-Drug Interactions
(Source H McIlleron)
Combined toxicities
Example of Linezolidbull CNS toxicity EFVbull Peripheral neuropathy DDI D4Tbull Lactic acidosis D4Tbull Myelosuppression ZDV
(Source H McIlleron)
Role of adjunctive immunotherapy
bull Shortening the duration of TB treatment bull Improve treatment success of M(X)DR TBbull Reduce clinical complicationsbull Reduce rate of recurrent TB
Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
GMP manufacturing capacity existsIvIgHE2000 M vaccaeanti-IL-4 RUTI
GMP capacity to be establishedhsp65 DNA vaccine
OtherDzherelo
Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
GMP manufacturing capacity existsIvIgHE2000 M vaccaeanti-IL-4 RUTI
GMP capacity to be establishedhsp65 DNA vaccine
OtherDzherelo
bull Thalidomide analogsndash Inhibit TNFα which is essential for granuloma
formationbull Entanercept (soluble TNF receptor)bull High dose prednisone
Concernsbull Requires concomitant bactericidal therapybull Agents inhibit protective immunity thereby
facilitating growth of organismsbull immunosuppression may result in OIs
Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
Supplementing effector cytokines to assist with antimicrobial activityRh-IFN-γ amp αRh-IL-2Rh-GM-CSFIL-12
Preventing HIV associated TB
Latent TB infection
TB disease
Treatment of latent TB infection
bull Isoniazid preventive therapy
Restore boost protective immunitybull ARTbull PrePost exposure TB vaccines
Isoniazid preventive therapy
bull Good safety profilebull Effective cheap amp readily availablebull Public health benefitBUTbull Requires a long treatment periodbull TB rates remain high in pts with advanced
HIV diseasebull Limited durabilitybull Adherence problematicbull Concern about promoting resistance
bull Efficacy compared to INH
TB incidence rate ratio (RR)minus INH (13) RR = 067minus INH + RIF (2) RR = 041minus RIF + PZA (4) RR = 054minus INH RIF + PZA (1) RR = 048
bull Increased side effects resulting in discontinuation
Multi-drug TB preventive therapyregimens
LTBI with MDRXDR TB
bull MDR TB increased globallybull Close contacts of MDRXDR TB patients are
at increased risk of becoming infectedbull PLHIV infected with MDRXDR TB are at
high risk of progressing to diseasebull Almost no data and inconsistent
international guidelines for treating contacts of MDR TB patients
HIV associated MDR amp XDR TB in SA
(N Gandhi Am J Resp Crit Care Med 2009)
Treatment of LTBIbull Effective tolerable ultra short course
treatment for DS LTBI requiredndash Mouse model of LTBI
(Eric Nuermberger) bull JgtRgtRHbull J=P=HPbull JPgtPZ
bull Effective treatment for LTBI with MDRXDR TB urgently neededndash need to evaluate regimens in mouse model
0003
006009
0003
006009
01
10
100
1000
10000
New TB cases
million in 2050
Treatment ratelatentyr
Vaccinations uninfected yr
ELIMINATING TB BY 2050BY PREVENTING INFECTION AND TREATING LATENT
INFECTIONEliminating TB by 2050Requires both PT and vaccines
M
8
L
O
Q
P
Control Group05mm 3 lesions1mm 25 lesions2mm 6 lesions
05mm 18 lesions1mm 8 lesions2mm 3 lesions
05mm 53 lesions1mm 13 lesions2mm 3 lesions
05mm 4 lesions1mm 1 lesions2mm 3 lesions
05mm 4 lesions1mm 3 lesions2mm 1 lesion
05mm 7 lesions1mm 4 lesions
05mm 24 lesions1mm 75 lesions2mm 10 lesionsgt2 2 (3mm) lesionsCoalescent 1 (4mm)
lesions R
Left Lung Right Lung
11
112
869
29
34
N
M
L
NO
Q
Qx Group05mm 1 lesion
05mm 5 lesions1mm 4 lesions2mm 1 lesion
05mm 5 lesions1mm 5 lesions2mm 1 lesion
05mm 1 lesion
1mm 1 lesion
05mm 8 lesions1mm 38 lesions2mm 2 lesionsgt2 3 (3mm) 1 (5mm)
1(6mm) lesionsCoalescent 1 (5mm) lesion
M
P
Left Lung Right Lung
1
54
1
11
10
1
R
L
NOR
Q
P
RUTI Group05mm 1 lesion
05mm 3 lesions1mm 3 lesions
05mm 1 lesion1mm 2 lesions
gt2mm 1 (3mm) lesion
05mm 6 lesions1mm 20 lesions2mm 8 lesionsgt2 2 (3mm) 1 (4mm)
lesions
M
Left Lung Right Lung
35 3
6
11
05mm 1mm 2mm gt2 Coalescent
Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
INH x 4weeksbull reduced granulomabull Reduced dissemination of infectionbull Retarded evolution of granulomabullDid not induce TB specific immunity
INH x 4wks + RUTI x 2bull reduced granulomabullReduced dissemination of infectionbull Promoted evolution of granulomabull Induced TB specific immunity
(Gill O PLoS ONE 5(4) e10030 doi101371journalpone0010030)
Conclusion
bull HIV associated TB accounts for the vast majority of TB in sub-Saharan Africa
bull Need new safe short effective regimens for HIV associated TB including MXDR TB
bull Use of adjunctive immunotherapy should be evaluated
bull Need new safe short effective regimens for treating LTBI particularly for DR TB
bull Therapeutic TB vaccines required
Acknowledgements
bull Helen McIlleronbull Ann Ginsburg
- Issues in TB Drug DevelopmentTBHIV
- Presentation outline
- SA has one of the worst TB epidemics in the world
- Integrated TB and HIV treatment saves lives
- Projected use of PI-based ART
- Slide Number 6
- Effect of IPT and ART on TB incidence and mortality
- Effect of IPT and ART on TB incidence and mortality
- Reduction in TB incidence with 36 vs 6 months IPT
- Reduction in TB incidence with 36 vs 6 months IPT
- New drugs amp regimens required for HIV associated TB
- Rifapentine ndash food interactions
- Potential interactions bw fluroquinolones and antiretrovirals
- PXR regulates drug-metabolizing enzymes
- Rifampicin is a potent activator of PXR
- Drug-Drug Interactions
- Combined toxicities
- Role of adjunctive immunotherapy
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
- Supplementing effector cytokines to assist with antimicrobial activity
- Preventing HIV associated TB
- Isoniazid preventive therapy
- Slide Number 25
- LTBI with MDRXDR TB
- Slide Number 27
- Treatment of LTBI
- Slide Number 29
- Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
- Conclusion
- Acknowledgements
-
Reference
PPD+
PPD-
PPD-unknown
Overall
TB
Relative Risk (Fixed) amp 95 CI
038
083
081
095
Death
08
102
084
10 10
064
Efficacy of TB preventive therapy among HIV-infected individuals
Woldehanna 2004 Cochrane review
Effect of IPT and ART on TB incidence and mortality
Golub AIDS2008 Incidence 100py aHR (95 CI)
No IPTART 71 1
ART 46 036 (025-05)
ARTIPT 11 011 (002-08)
Innes CROI 2010 Mortality100py aHR (95 CI)
ART 111 1
ARTIPT 35 047 (03-07)
Effect of IPT and ART on TB incidence and mortality
Golub AIDS2008 Incidence 100py aHR (95 CI)
No IPTART 71 1
ART 46 036 (025-05)
ARTIPT 11 011 (002-08)
Innes CROI 2010 Mortality100py aHR (95 CI)
ART 111 1
ARTIPT 35 047 (03-07)
Author Location Intentionto treat
PerProtocol
Martinson Soweto 19 69
Samandari BotswanaAll 54 65TST+ 93TST- 19
(Martinson et al Union conference 2008 CROI 2009)(Samandari et al Union Conference 2009)
Reduction in TB incidence with 36 vs 6 months IPT
Author Location Intentionto treat
PerProtocol
Martinson Soweto 19 69
Samandari BotswanaAll 54 65TST+ 93TST- 19
(Martinson et al Union conference 2008 CROI 2009)(Samandari et al Union Conference 2009)
Reduction in TB incidence with 36 vs 6 months IPT
New drugs amp regimens required for HIV associated TB
bull To increase ndash Efficacyndash Safety ndash tolerability
bull To decrease ndash treatment durationndash Complexityndash drug-drug interactions ndash cost
Rifapentine ndash food interactions
0
5
10
15
20
25
30
0 10 20 30 40 50 60
RFP
pla
sma
conc
(m
gL)
Time after dose (h)
0
2
4
6
8
10
12
14
0 10 20 30 40 50 60
25-D
RFP
pla
sma
conc
(m
gL)
Time after dose (h)
High fat meal
Bulk_Low fat meal
Bulk_High fat
Chicken soup
Fasted state
Zvada SP Antimicrob Agents Chemother 2010 54(8)3390-4
+86 (RSE=20)
Potential interactions bw fluroquinolones and antiretrovirals
bullSafety interactionsndash QT prolongation (LPVr)ndash Dysglycaemia (PIs)
bullPK interactionsndash chelation by multivalent anions (buffered ddI)ndash moxifloxacin is a UGT SGT substrate
Antimicrob Agents Chemother 2007 512861ndash6 and 2008 524037-42 J Antimicrob Chemother 2007 601398-401 Clin Infect Dis 2007 451001ndash7 J Int AIDS Soc 2008 11 S95 (abstr) J Infect
2008 57 78-81
CYP2B6
CYP2C9CYP2C8
CYP2B9
CYP3A4CYP3A7
UGTs
GSTs
SULTs
PXR
APBL
PXR regulates drug-metabolizing enzymes
MRP2
OATP2
MDR1PHASE II
PHASE IEFFLUX
TRANSPORTERS
INFLUX
BASELINE ACTIVITYPXR expressionenzymes activityamp transporters
(Pharmacogenomics 2008 9 1695ndash1709 Drug Metab Dispos 2006 101756-63 amp 2007 351400-7)
OATP1B1
Rifampicin is a potent activator of PXR
CYP2B6
CYP2C9CYP2C8
CYP2B9
CYP3A4
UGTs
GSTs
SULTs
PXR-RXR
APBL
MRP2
OATP2
MDR1
Activating ligands trigger altered expression of multiple of enzymes and transporters with
compound effects on substrate concentrations
DRUG
RIF
OATP1B1
CYP3A7
J Pharmacol Exp Ther 2003 304 223-28
Drug InteractionsDiarylquinolines(TMC207)
bullCYP 3A4 SubstratebullNo PK interactions with HZbullPK studies with EFV NVP LPVr awaited
Ethylene Diamines (SQ-109)
CYP 2D6 CYP 2C19 substrate
Nitroimidazoles (PA-824 OPC-67683)
Not metabolized by or interfere with CYP enzymes
oxazolidinones (PNU-100480 Linezolid )
Mono Aminine Oxidase InhibitorsNot metabolized by or interfere with drug metabolizing enzymes
Drug-Drug Interactions
(Source H McIlleron)
Combined toxicities
Example of Linezolidbull CNS toxicity EFVbull Peripheral neuropathy DDI D4Tbull Lactic acidosis D4Tbull Myelosuppression ZDV
(Source H McIlleron)
Role of adjunctive immunotherapy
bull Shortening the duration of TB treatment bull Improve treatment success of M(X)DR TBbull Reduce clinical complicationsbull Reduce rate of recurrent TB
Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
GMP manufacturing capacity existsIvIgHE2000 M vaccaeanti-IL-4 RUTI
GMP capacity to be establishedhsp65 DNA vaccine
OtherDzherelo
Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
GMP manufacturing capacity existsIvIgHE2000 M vaccaeanti-IL-4 RUTI
GMP capacity to be establishedhsp65 DNA vaccine
OtherDzherelo
bull Thalidomide analogsndash Inhibit TNFα which is essential for granuloma
formationbull Entanercept (soluble TNF receptor)bull High dose prednisone
Concernsbull Requires concomitant bactericidal therapybull Agents inhibit protective immunity thereby
facilitating growth of organismsbull immunosuppression may result in OIs
Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
Supplementing effector cytokines to assist with antimicrobial activityRh-IFN-γ amp αRh-IL-2Rh-GM-CSFIL-12
Preventing HIV associated TB
Latent TB infection
TB disease
Treatment of latent TB infection
bull Isoniazid preventive therapy
Restore boost protective immunitybull ARTbull PrePost exposure TB vaccines
Isoniazid preventive therapy
bull Good safety profilebull Effective cheap amp readily availablebull Public health benefitBUTbull Requires a long treatment periodbull TB rates remain high in pts with advanced
HIV diseasebull Limited durabilitybull Adherence problematicbull Concern about promoting resistance
bull Efficacy compared to INH
TB incidence rate ratio (RR)minus INH (13) RR = 067minus INH + RIF (2) RR = 041minus RIF + PZA (4) RR = 054minus INH RIF + PZA (1) RR = 048
bull Increased side effects resulting in discontinuation
Multi-drug TB preventive therapyregimens
LTBI with MDRXDR TB
bull MDR TB increased globallybull Close contacts of MDRXDR TB patients are
at increased risk of becoming infectedbull PLHIV infected with MDRXDR TB are at
high risk of progressing to diseasebull Almost no data and inconsistent
international guidelines for treating contacts of MDR TB patients
HIV associated MDR amp XDR TB in SA
(N Gandhi Am J Resp Crit Care Med 2009)
Treatment of LTBIbull Effective tolerable ultra short course
treatment for DS LTBI requiredndash Mouse model of LTBI
(Eric Nuermberger) bull JgtRgtRHbull J=P=HPbull JPgtPZ
bull Effective treatment for LTBI with MDRXDR TB urgently neededndash need to evaluate regimens in mouse model
0003
006009
0003
006009
01
10
100
1000
10000
New TB cases
million in 2050
Treatment ratelatentyr
Vaccinations uninfected yr
ELIMINATING TB BY 2050BY PREVENTING INFECTION AND TREATING LATENT
INFECTIONEliminating TB by 2050Requires both PT and vaccines
M
8
L
O
Q
P
Control Group05mm 3 lesions1mm 25 lesions2mm 6 lesions
05mm 18 lesions1mm 8 lesions2mm 3 lesions
05mm 53 lesions1mm 13 lesions2mm 3 lesions
05mm 4 lesions1mm 1 lesions2mm 3 lesions
05mm 4 lesions1mm 3 lesions2mm 1 lesion
05mm 7 lesions1mm 4 lesions
05mm 24 lesions1mm 75 lesions2mm 10 lesionsgt2 2 (3mm) lesionsCoalescent 1 (4mm)
lesions R
Left Lung Right Lung
11
112
869
29
34
N
M
L
NO
Q
Qx Group05mm 1 lesion
05mm 5 lesions1mm 4 lesions2mm 1 lesion
05mm 5 lesions1mm 5 lesions2mm 1 lesion
05mm 1 lesion
1mm 1 lesion
05mm 8 lesions1mm 38 lesions2mm 2 lesionsgt2 3 (3mm) 1 (5mm)
1(6mm) lesionsCoalescent 1 (5mm) lesion
M
P
Left Lung Right Lung
1
54
1
11
10
1
R
L
NOR
Q
P
RUTI Group05mm 1 lesion
05mm 3 lesions1mm 3 lesions
05mm 1 lesion1mm 2 lesions
gt2mm 1 (3mm) lesion
05mm 6 lesions1mm 20 lesions2mm 8 lesionsgt2 2 (3mm) 1 (4mm)
lesions
M
Left Lung Right Lung
35 3
6
11
05mm 1mm 2mm gt2 Coalescent
Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
INH x 4weeksbull reduced granulomabull Reduced dissemination of infectionbull Retarded evolution of granulomabullDid not induce TB specific immunity
INH x 4wks + RUTI x 2bull reduced granulomabullReduced dissemination of infectionbull Promoted evolution of granulomabull Induced TB specific immunity
(Gill O PLoS ONE 5(4) e10030 doi101371journalpone0010030)
Conclusion
bull HIV associated TB accounts for the vast majority of TB in sub-Saharan Africa
bull Need new safe short effective regimens for HIV associated TB including MXDR TB
bull Use of adjunctive immunotherapy should be evaluated
bull Need new safe short effective regimens for treating LTBI particularly for DR TB
bull Therapeutic TB vaccines required
Acknowledgements
bull Helen McIlleronbull Ann Ginsburg
- Issues in TB Drug DevelopmentTBHIV
- Presentation outline
- SA has one of the worst TB epidemics in the world
- Integrated TB and HIV treatment saves lives
- Projected use of PI-based ART
- Slide Number 6
- Effect of IPT and ART on TB incidence and mortality
- Effect of IPT and ART on TB incidence and mortality
- Reduction in TB incidence with 36 vs 6 months IPT
- Reduction in TB incidence with 36 vs 6 months IPT
- New drugs amp regimens required for HIV associated TB
- Rifapentine ndash food interactions
- Potential interactions bw fluroquinolones and antiretrovirals
- PXR regulates drug-metabolizing enzymes
- Rifampicin is a potent activator of PXR
- Drug-Drug Interactions
- Combined toxicities
- Role of adjunctive immunotherapy
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
- Supplementing effector cytokines to assist with antimicrobial activity
- Preventing HIV associated TB
- Isoniazid preventive therapy
- Slide Number 25
- LTBI with MDRXDR TB
- Slide Number 27
- Treatment of LTBI
- Slide Number 29
- Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
- Conclusion
- Acknowledgements
-
Effect of IPT and ART on TB incidence and mortality
Golub AIDS2008 Incidence 100py aHR (95 CI)
No IPTART 71 1
ART 46 036 (025-05)
ARTIPT 11 011 (002-08)
Innes CROI 2010 Mortality100py aHR (95 CI)
ART 111 1
ARTIPT 35 047 (03-07)
Effect of IPT and ART on TB incidence and mortality
Golub AIDS2008 Incidence 100py aHR (95 CI)
No IPTART 71 1
ART 46 036 (025-05)
ARTIPT 11 011 (002-08)
Innes CROI 2010 Mortality100py aHR (95 CI)
ART 111 1
ARTIPT 35 047 (03-07)
Author Location Intentionto treat
PerProtocol
Martinson Soweto 19 69
Samandari BotswanaAll 54 65TST+ 93TST- 19
(Martinson et al Union conference 2008 CROI 2009)(Samandari et al Union Conference 2009)
Reduction in TB incidence with 36 vs 6 months IPT
Author Location Intentionto treat
PerProtocol
Martinson Soweto 19 69
Samandari BotswanaAll 54 65TST+ 93TST- 19
(Martinson et al Union conference 2008 CROI 2009)(Samandari et al Union Conference 2009)
Reduction in TB incidence with 36 vs 6 months IPT
New drugs amp regimens required for HIV associated TB
bull To increase ndash Efficacyndash Safety ndash tolerability
bull To decrease ndash treatment durationndash Complexityndash drug-drug interactions ndash cost
Rifapentine ndash food interactions
0
5
10
15
20
25
30
0 10 20 30 40 50 60
RFP
pla
sma
conc
(m
gL)
Time after dose (h)
0
2
4
6
8
10
12
14
0 10 20 30 40 50 60
25-D
RFP
pla
sma
conc
(m
gL)
Time after dose (h)
High fat meal
Bulk_Low fat meal
Bulk_High fat
Chicken soup
Fasted state
Zvada SP Antimicrob Agents Chemother 2010 54(8)3390-4
+86 (RSE=20)
Potential interactions bw fluroquinolones and antiretrovirals
bullSafety interactionsndash QT prolongation (LPVr)ndash Dysglycaemia (PIs)
bullPK interactionsndash chelation by multivalent anions (buffered ddI)ndash moxifloxacin is a UGT SGT substrate
Antimicrob Agents Chemother 2007 512861ndash6 and 2008 524037-42 J Antimicrob Chemother 2007 601398-401 Clin Infect Dis 2007 451001ndash7 J Int AIDS Soc 2008 11 S95 (abstr) J Infect
2008 57 78-81
CYP2B6
CYP2C9CYP2C8
CYP2B9
CYP3A4CYP3A7
UGTs
GSTs
SULTs
PXR
APBL
PXR regulates drug-metabolizing enzymes
MRP2
OATP2
MDR1PHASE II
PHASE IEFFLUX
TRANSPORTERS
INFLUX
BASELINE ACTIVITYPXR expressionenzymes activityamp transporters
(Pharmacogenomics 2008 9 1695ndash1709 Drug Metab Dispos 2006 101756-63 amp 2007 351400-7)
OATP1B1
Rifampicin is a potent activator of PXR
CYP2B6
CYP2C9CYP2C8
CYP2B9
CYP3A4
UGTs
GSTs
SULTs
PXR-RXR
APBL
MRP2
OATP2
MDR1
Activating ligands trigger altered expression of multiple of enzymes and transporters with
compound effects on substrate concentrations
DRUG
RIF
OATP1B1
CYP3A7
J Pharmacol Exp Ther 2003 304 223-28
Drug InteractionsDiarylquinolines(TMC207)
bullCYP 3A4 SubstratebullNo PK interactions with HZbullPK studies with EFV NVP LPVr awaited
Ethylene Diamines (SQ-109)
CYP 2D6 CYP 2C19 substrate
Nitroimidazoles (PA-824 OPC-67683)
Not metabolized by or interfere with CYP enzymes
oxazolidinones (PNU-100480 Linezolid )
Mono Aminine Oxidase InhibitorsNot metabolized by or interfere with drug metabolizing enzymes
Drug-Drug Interactions
(Source H McIlleron)
Combined toxicities
Example of Linezolidbull CNS toxicity EFVbull Peripheral neuropathy DDI D4Tbull Lactic acidosis D4Tbull Myelosuppression ZDV
(Source H McIlleron)
Role of adjunctive immunotherapy
bull Shortening the duration of TB treatment bull Improve treatment success of M(X)DR TBbull Reduce clinical complicationsbull Reduce rate of recurrent TB
Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
GMP manufacturing capacity existsIvIgHE2000 M vaccaeanti-IL-4 RUTI
GMP capacity to be establishedhsp65 DNA vaccine
OtherDzherelo
Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
GMP manufacturing capacity existsIvIgHE2000 M vaccaeanti-IL-4 RUTI
GMP capacity to be establishedhsp65 DNA vaccine
OtherDzherelo
bull Thalidomide analogsndash Inhibit TNFα which is essential for granuloma
formationbull Entanercept (soluble TNF receptor)bull High dose prednisone
Concernsbull Requires concomitant bactericidal therapybull Agents inhibit protective immunity thereby
facilitating growth of organismsbull immunosuppression may result in OIs
Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
Supplementing effector cytokines to assist with antimicrobial activityRh-IFN-γ amp αRh-IL-2Rh-GM-CSFIL-12
Preventing HIV associated TB
Latent TB infection
TB disease
Treatment of latent TB infection
bull Isoniazid preventive therapy
Restore boost protective immunitybull ARTbull PrePost exposure TB vaccines
Isoniazid preventive therapy
bull Good safety profilebull Effective cheap amp readily availablebull Public health benefitBUTbull Requires a long treatment periodbull TB rates remain high in pts with advanced
HIV diseasebull Limited durabilitybull Adherence problematicbull Concern about promoting resistance
bull Efficacy compared to INH
TB incidence rate ratio (RR)minus INH (13) RR = 067minus INH + RIF (2) RR = 041minus RIF + PZA (4) RR = 054minus INH RIF + PZA (1) RR = 048
bull Increased side effects resulting in discontinuation
Multi-drug TB preventive therapyregimens
LTBI with MDRXDR TB
bull MDR TB increased globallybull Close contacts of MDRXDR TB patients are
at increased risk of becoming infectedbull PLHIV infected with MDRXDR TB are at
high risk of progressing to diseasebull Almost no data and inconsistent
international guidelines for treating contacts of MDR TB patients
HIV associated MDR amp XDR TB in SA
(N Gandhi Am J Resp Crit Care Med 2009)
Treatment of LTBIbull Effective tolerable ultra short course
treatment for DS LTBI requiredndash Mouse model of LTBI
(Eric Nuermberger) bull JgtRgtRHbull J=P=HPbull JPgtPZ
bull Effective treatment for LTBI with MDRXDR TB urgently neededndash need to evaluate regimens in mouse model
0003
006009
0003
006009
01
10
100
1000
10000
New TB cases
million in 2050
Treatment ratelatentyr
Vaccinations uninfected yr
ELIMINATING TB BY 2050BY PREVENTING INFECTION AND TREATING LATENT
INFECTIONEliminating TB by 2050Requires both PT and vaccines
M
8
L
O
Q
P
Control Group05mm 3 lesions1mm 25 lesions2mm 6 lesions
05mm 18 lesions1mm 8 lesions2mm 3 lesions
05mm 53 lesions1mm 13 lesions2mm 3 lesions
05mm 4 lesions1mm 1 lesions2mm 3 lesions
05mm 4 lesions1mm 3 lesions2mm 1 lesion
05mm 7 lesions1mm 4 lesions
05mm 24 lesions1mm 75 lesions2mm 10 lesionsgt2 2 (3mm) lesionsCoalescent 1 (4mm)
lesions R
Left Lung Right Lung
11
112
869
29
34
N
M
L
NO
Q
Qx Group05mm 1 lesion
05mm 5 lesions1mm 4 lesions2mm 1 lesion
05mm 5 lesions1mm 5 lesions2mm 1 lesion
05mm 1 lesion
1mm 1 lesion
05mm 8 lesions1mm 38 lesions2mm 2 lesionsgt2 3 (3mm) 1 (5mm)
1(6mm) lesionsCoalescent 1 (5mm) lesion
M
P
Left Lung Right Lung
1
54
1
11
10
1
R
L
NOR
Q
P
RUTI Group05mm 1 lesion
05mm 3 lesions1mm 3 lesions
05mm 1 lesion1mm 2 lesions
gt2mm 1 (3mm) lesion
05mm 6 lesions1mm 20 lesions2mm 8 lesionsgt2 2 (3mm) 1 (4mm)
lesions
M
Left Lung Right Lung
35 3
6
11
05mm 1mm 2mm gt2 Coalescent
Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
INH x 4weeksbull reduced granulomabull Reduced dissemination of infectionbull Retarded evolution of granulomabullDid not induce TB specific immunity
INH x 4wks + RUTI x 2bull reduced granulomabullReduced dissemination of infectionbull Promoted evolution of granulomabull Induced TB specific immunity
(Gill O PLoS ONE 5(4) e10030 doi101371journalpone0010030)
Conclusion
bull HIV associated TB accounts for the vast majority of TB in sub-Saharan Africa
bull Need new safe short effective regimens for HIV associated TB including MXDR TB
bull Use of adjunctive immunotherapy should be evaluated
bull Need new safe short effective regimens for treating LTBI particularly for DR TB
bull Therapeutic TB vaccines required
Acknowledgements
bull Helen McIlleronbull Ann Ginsburg
- Issues in TB Drug DevelopmentTBHIV
- Presentation outline
- SA has one of the worst TB epidemics in the world
- Integrated TB and HIV treatment saves lives
- Projected use of PI-based ART
- Slide Number 6
- Effect of IPT and ART on TB incidence and mortality
- Effect of IPT and ART on TB incidence and mortality
- Reduction in TB incidence with 36 vs 6 months IPT
- Reduction in TB incidence with 36 vs 6 months IPT
- New drugs amp regimens required for HIV associated TB
- Rifapentine ndash food interactions
- Potential interactions bw fluroquinolones and antiretrovirals
- PXR regulates drug-metabolizing enzymes
- Rifampicin is a potent activator of PXR
- Drug-Drug Interactions
- Combined toxicities
- Role of adjunctive immunotherapy
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
- Supplementing effector cytokines to assist with antimicrobial activity
- Preventing HIV associated TB
- Isoniazid preventive therapy
- Slide Number 25
- LTBI with MDRXDR TB
- Slide Number 27
- Treatment of LTBI
- Slide Number 29
- Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
- Conclusion
- Acknowledgements
-
Effect of IPT and ART on TB incidence and mortality
Golub AIDS2008 Incidence 100py aHR (95 CI)
No IPTART 71 1
ART 46 036 (025-05)
ARTIPT 11 011 (002-08)
Innes CROI 2010 Mortality100py aHR (95 CI)
ART 111 1
ARTIPT 35 047 (03-07)
Author Location Intentionto treat
PerProtocol
Martinson Soweto 19 69
Samandari BotswanaAll 54 65TST+ 93TST- 19
(Martinson et al Union conference 2008 CROI 2009)(Samandari et al Union Conference 2009)
Reduction in TB incidence with 36 vs 6 months IPT
Author Location Intentionto treat
PerProtocol
Martinson Soweto 19 69
Samandari BotswanaAll 54 65TST+ 93TST- 19
(Martinson et al Union conference 2008 CROI 2009)(Samandari et al Union Conference 2009)
Reduction in TB incidence with 36 vs 6 months IPT
New drugs amp regimens required for HIV associated TB
bull To increase ndash Efficacyndash Safety ndash tolerability
bull To decrease ndash treatment durationndash Complexityndash drug-drug interactions ndash cost
Rifapentine ndash food interactions
0
5
10
15
20
25
30
0 10 20 30 40 50 60
RFP
pla
sma
conc
(m
gL)
Time after dose (h)
0
2
4
6
8
10
12
14
0 10 20 30 40 50 60
25-D
RFP
pla
sma
conc
(m
gL)
Time after dose (h)
High fat meal
Bulk_Low fat meal
Bulk_High fat
Chicken soup
Fasted state
Zvada SP Antimicrob Agents Chemother 2010 54(8)3390-4
+86 (RSE=20)
Potential interactions bw fluroquinolones and antiretrovirals
bullSafety interactionsndash QT prolongation (LPVr)ndash Dysglycaemia (PIs)
bullPK interactionsndash chelation by multivalent anions (buffered ddI)ndash moxifloxacin is a UGT SGT substrate
Antimicrob Agents Chemother 2007 512861ndash6 and 2008 524037-42 J Antimicrob Chemother 2007 601398-401 Clin Infect Dis 2007 451001ndash7 J Int AIDS Soc 2008 11 S95 (abstr) J Infect
2008 57 78-81
CYP2B6
CYP2C9CYP2C8
CYP2B9
CYP3A4CYP3A7
UGTs
GSTs
SULTs
PXR
APBL
PXR regulates drug-metabolizing enzymes
MRP2
OATP2
MDR1PHASE II
PHASE IEFFLUX
TRANSPORTERS
INFLUX
BASELINE ACTIVITYPXR expressionenzymes activityamp transporters
(Pharmacogenomics 2008 9 1695ndash1709 Drug Metab Dispos 2006 101756-63 amp 2007 351400-7)
OATP1B1
Rifampicin is a potent activator of PXR
CYP2B6
CYP2C9CYP2C8
CYP2B9
CYP3A4
UGTs
GSTs
SULTs
PXR-RXR
APBL
MRP2
OATP2
MDR1
Activating ligands trigger altered expression of multiple of enzymes and transporters with
compound effects on substrate concentrations
DRUG
RIF
OATP1B1
CYP3A7
J Pharmacol Exp Ther 2003 304 223-28
Drug InteractionsDiarylquinolines(TMC207)
bullCYP 3A4 SubstratebullNo PK interactions with HZbullPK studies with EFV NVP LPVr awaited
Ethylene Diamines (SQ-109)
CYP 2D6 CYP 2C19 substrate
Nitroimidazoles (PA-824 OPC-67683)
Not metabolized by or interfere with CYP enzymes
oxazolidinones (PNU-100480 Linezolid )
Mono Aminine Oxidase InhibitorsNot metabolized by or interfere with drug metabolizing enzymes
Drug-Drug Interactions
(Source H McIlleron)
Combined toxicities
Example of Linezolidbull CNS toxicity EFVbull Peripheral neuropathy DDI D4Tbull Lactic acidosis D4Tbull Myelosuppression ZDV
(Source H McIlleron)
Role of adjunctive immunotherapy
bull Shortening the duration of TB treatment bull Improve treatment success of M(X)DR TBbull Reduce clinical complicationsbull Reduce rate of recurrent TB
Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
GMP manufacturing capacity existsIvIgHE2000 M vaccaeanti-IL-4 RUTI
GMP capacity to be establishedhsp65 DNA vaccine
OtherDzherelo
Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
GMP manufacturing capacity existsIvIgHE2000 M vaccaeanti-IL-4 RUTI
GMP capacity to be establishedhsp65 DNA vaccine
OtherDzherelo
bull Thalidomide analogsndash Inhibit TNFα which is essential for granuloma
formationbull Entanercept (soluble TNF receptor)bull High dose prednisone
Concernsbull Requires concomitant bactericidal therapybull Agents inhibit protective immunity thereby
facilitating growth of organismsbull immunosuppression may result in OIs
Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
Supplementing effector cytokines to assist with antimicrobial activityRh-IFN-γ amp αRh-IL-2Rh-GM-CSFIL-12
Preventing HIV associated TB
Latent TB infection
TB disease
Treatment of latent TB infection
bull Isoniazid preventive therapy
Restore boost protective immunitybull ARTbull PrePost exposure TB vaccines
Isoniazid preventive therapy
bull Good safety profilebull Effective cheap amp readily availablebull Public health benefitBUTbull Requires a long treatment periodbull TB rates remain high in pts with advanced
HIV diseasebull Limited durabilitybull Adherence problematicbull Concern about promoting resistance
bull Efficacy compared to INH
TB incidence rate ratio (RR)minus INH (13) RR = 067minus INH + RIF (2) RR = 041minus RIF + PZA (4) RR = 054minus INH RIF + PZA (1) RR = 048
bull Increased side effects resulting in discontinuation
Multi-drug TB preventive therapyregimens
LTBI with MDRXDR TB
bull MDR TB increased globallybull Close contacts of MDRXDR TB patients are
at increased risk of becoming infectedbull PLHIV infected with MDRXDR TB are at
high risk of progressing to diseasebull Almost no data and inconsistent
international guidelines for treating contacts of MDR TB patients
HIV associated MDR amp XDR TB in SA
(N Gandhi Am J Resp Crit Care Med 2009)
Treatment of LTBIbull Effective tolerable ultra short course
treatment for DS LTBI requiredndash Mouse model of LTBI
(Eric Nuermberger) bull JgtRgtRHbull J=P=HPbull JPgtPZ
bull Effective treatment for LTBI with MDRXDR TB urgently neededndash need to evaluate regimens in mouse model
0003
006009
0003
006009
01
10
100
1000
10000
New TB cases
million in 2050
Treatment ratelatentyr
Vaccinations uninfected yr
ELIMINATING TB BY 2050BY PREVENTING INFECTION AND TREATING LATENT
INFECTIONEliminating TB by 2050Requires both PT and vaccines
M
8
L
O
Q
P
Control Group05mm 3 lesions1mm 25 lesions2mm 6 lesions
05mm 18 lesions1mm 8 lesions2mm 3 lesions
05mm 53 lesions1mm 13 lesions2mm 3 lesions
05mm 4 lesions1mm 1 lesions2mm 3 lesions
05mm 4 lesions1mm 3 lesions2mm 1 lesion
05mm 7 lesions1mm 4 lesions
05mm 24 lesions1mm 75 lesions2mm 10 lesionsgt2 2 (3mm) lesionsCoalescent 1 (4mm)
lesions R
Left Lung Right Lung
11
112
869
29
34
N
M
L
NO
Q
Qx Group05mm 1 lesion
05mm 5 lesions1mm 4 lesions2mm 1 lesion
05mm 5 lesions1mm 5 lesions2mm 1 lesion
05mm 1 lesion
1mm 1 lesion
05mm 8 lesions1mm 38 lesions2mm 2 lesionsgt2 3 (3mm) 1 (5mm)
1(6mm) lesionsCoalescent 1 (5mm) lesion
M
P
Left Lung Right Lung
1
54
1
11
10
1
R
L
NOR
Q
P
RUTI Group05mm 1 lesion
05mm 3 lesions1mm 3 lesions
05mm 1 lesion1mm 2 lesions
gt2mm 1 (3mm) lesion
05mm 6 lesions1mm 20 lesions2mm 8 lesionsgt2 2 (3mm) 1 (4mm)
lesions
M
Left Lung Right Lung
35 3
6
11
05mm 1mm 2mm gt2 Coalescent
Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
INH x 4weeksbull reduced granulomabull Reduced dissemination of infectionbull Retarded evolution of granulomabullDid not induce TB specific immunity
INH x 4wks + RUTI x 2bull reduced granulomabullReduced dissemination of infectionbull Promoted evolution of granulomabull Induced TB specific immunity
(Gill O PLoS ONE 5(4) e10030 doi101371journalpone0010030)
Conclusion
bull HIV associated TB accounts for the vast majority of TB in sub-Saharan Africa
bull Need new safe short effective regimens for HIV associated TB including MXDR TB
bull Use of adjunctive immunotherapy should be evaluated
bull Need new safe short effective regimens for treating LTBI particularly for DR TB
bull Therapeutic TB vaccines required
Acknowledgements
bull Helen McIlleronbull Ann Ginsburg
- Issues in TB Drug DevelopmentTBHIV
- Presentation outline
- SA has one of the worst TB epidemics in the world
- Integrated TB and HIV treatment saves lives
- Projected use of PI-based ART
- Slide Number 6
- Effect of IPT and ART on TB incidence and mortality
- Effect of IPT and ART on TB incidence and mortality
- Reduction in TB incidence with 36 vs 6 months IPT
- Reduction in TB incidence with 36 vs 6 months IPT
- New drugs amp regimens required for HIV associated TB
- Rifapentine ndash food interactions
- Potential interactions bw fluroquinolones and antiretrovirals
- PXR regulates drug-metabolizing enzymes
- Rifampicin is a potent activator of PXR
- Drug-Drug Interactions
- Combined toxicities
- Role of adjunctive immunotherapy
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
- Supplementing effector cytokines to assist with antimicrobial activity
- Preventing HIV associated TB
- Isoniazid preventive therapy
- Slide Number 25
- LTBI with MDRXDR TB
- Slide Number 27
- Treatment of LTBI
- Slide Number 29
- Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
- Conclusion
- Acknowledgements
-
Author Location Intentionto treat
PerProtocol
Martinson Soweto 19 69
Samandari BotswanaAll 54 65TST+ 93TST- 19
(Martinson et al Union conference 2008 CROI 2009)(Samandari et al Union Conference 2009)
Reduction in TB incidence with 36 vs 6 months IPT
Author Location Intentionto treat
PerProtocol
Martinson Soweto 19 69
Samandari BotswanaAll 54 65TST+ 93TST- 19
(Martinson et al Union conference 2008 CROI 2009)(Samandari et al Union Conference 2009)
Reduction in TB incidence with 36 vs 6 months IPT
New drugs amp regimens required for HIV associated TB
bull To increase ndash Efficacyndash Safety ndash tolerability
bull To decrease ndash treatment durationndash Complexityndash drug-drug interactions ndash cost
Rifapentine ndash food interactions
0
5
10
15
20
25
30
0 10 20 30 40 50 60
RFP
pla
sma
conc
(m
gL)
Time after dose (h)
0
2
4
6
8
10
12
14
0 10 20 30 40 50 60
25-D
RFP
pla
sma
conc
(m
gL)
Time after dose (h)
High fat meal
Bulk_Low fat meal
Bulk_High fat
Chicken soup
Fasted state
Zvada SP Antimicrob Agents Chemother 2010 54(8)3390-4
+86 (RSE=20)
Potential interactions bw fluroquinolones and antiretrovirals
bullSafety interactionsndash QT prolongation (LPVr)ndash Dysglycaemia (PIs)
bullPK interactionsndash chelation by multivalent anions (buffered ddI)ndash moxifloxacin is a UGT SGT substrate
Antimicrob Agents Chemother 2007 512861ndash6 and 2008 524037-42 J Antimicrob Chemother 2007 601398-401 Clin Infect Dis 2007 451001ndash7 J Int AIDS Soc 2008 11 S95 (abstr) J Infect
2008 57 78-81
CYP2B6
CYP2C9CYP2C8
CYP2B9
CYP3A4CYP3A7
UGTs
GSTs
SULTs
PXR
APBL
PXR regulates drug-metabolizing enzymes
MRP2
OATP2
MDR1PHASE II
PHASE IEFFLUX
TRANSPORTERS
INFLUX
BASELINE ACTIVITYPXR expressionenzymes activityamp transporters
(Pharmacogenomics 2008 9 1695ndash1709 Drug Metab Dispos 2006 101756-63 amp 2007 351400-7)
OATP1B1
Rifampicin is a potent activator of PXR
CYP2B6
CYP2C9CYP2C8
CYP2B9
CYP3A4
UGTs
GSTs
SULTs
PXR-RXR
APBL
MRP2
OATP2
MDR1
Activating ligands trigger altered expression of multiple of enzymes and transporters with
compound effects on substrate concentrations
DRUG
RIF
OATP1B1
CYP3A7
J Pharmacol Exp Ther 2003 304 223-28
Drug InteractionsDiarylquinolines(TMC207)
bullCYP 3A4 SubstratebullNo PK interactions with HZbullPK studies with EFV NVP LPVr awaited
Ethylene Diamines (SQ-109)
CYP 2D6 CYP 2C19 substrate
Nitroimidazoles (PA-824 OPC-67683)
Not metabolized by or interfere with CYP enzymes
oxazolidinones (PNU-100480 Linezolid )
Mono Aminine Oxidase InhibitorsNot metabolized by or interfere with drug metabolizing enzymes
Drug-Drug Interactions
(Source H McIlleron)
Combined toxicities
Example of Linezolidbull CNS toxicity EFVbull Peripheral neuropathy DDI D4Tbull Lactic acidosis D4Tbull Myelosuppression ZDV
(Source H McIlleron)
Role of adjunctive immunotherapy
bull Shortening the duration of TB treatment bull Improve treatment success of M(X)DR TBbull Reduce clinical complicationsbull Reduce rate of recurrent TB
Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
GMP manufacturing capacity existsIvIgHE2000 M vaccaeanti-IL-4 RUTI
GMP capacity to be establishedhsp65 DNA vaccine
OtherDzherelo
Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
GMP manufacturing capacity existsIvIgHE2000 M vaccaeanti-IL-4 RUTI
GMP capacity to be establishedhsp65 DNA vaccine
OtherDzherelo
bull Thalidomide analogsndash Inhibit TNFα which is essential for granuloma
formationbull Entanercept (soluble TNF receptor)bull High dose prednisone
Concernsbull Requires concomitant bactericidal therapybull Agents inhibit protective immunity thereby
facilitating growth of organismsbull immunosuppression may result in OIs
Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
Supplementing effector cytokines to assist with antimicrobial activityRh-IFN-γ amp αRh-IL-2Rh-GM-CSFIL-12
Preventing HIV associated TB
Latent TB infection
TB disease
Treatment of latent TB infection
bull Isoniazid preventive therapy
Restore boost protective immunitybull ARTbull PrePost exposure TB vaccines
Isoniazid preventive therapy
bull Good safety profilebull Effective cheap amp readily availablebull Public health benefitBUTbull Requires a long treatment periodbull TB rates remain high in pts with advanced
HIV diseasebull Limited durabilitybull Adherence problematicbull Concern about promoting resistance
bull Efficacy compared to INH
TB incidence rate ratio (RR)minus INH (13) RR = 067minus INH + RIF (2) RR = 041minus RIF + PZA (4) RR = 054minus INH RIF + PZA (1) RR = 048
bull Increased side effects resulting in discontinuation
Multi-drug TB preventive therapyregimens
LTBI with MDRXDR TB
bull MDR TB increased globallybull Close contacts of MDRXDR TB patients are
at increased risk of becoming infectedbull PLHIV infected with MDRXDR TB are at
high risk of progressing to diseasebull Almost no data and inconsistent
international guidelines for treating contacts of MDR TB patients
HIV associated MDR amp XDR TB in SA
(N Gandhi Am J Resp Crit Care Med 2009)
Treatment of LTBIbull Effective tolerable ultra short course
treatment for DS LTBI requiredndash Mouse model of LTBI
(Eric Nuermberger) bull JgtRgtRHbull J=P=HPbull JPgtPZ
bull Effective treatment for LTBI with MDRXDR TB urgently neededndash need to evaluate regimens in mouse model
0003
006009
0003
006009
01
10
100
1000
10000
New TB cases
million in 2050
Treatment ratelatentyr
Vaccinations uninfected yr
ELIMINATING TB BY 2050BY PREVENTING INFECTION AND TREATING LATENT
INFECTIONEliminating TB by 2050Requires both PT and vaccines
M
8
L
O
Q
P
Control Group05mm 3 lesions1mm 25 lesions2mm 6 lesions
05mm 18 lesions1mm 8 lesions2mm 3 lesions
05mm 53 lesions1mm 13 lesions2mm 3 lesions
05mm 4 lesions1mm 1 lesions2mm 3 lesions
05mm 4 lesions1mm 3 lesions2mm 1 lesion
05mm 7 lesions1mm 4 lesions
05mm 24 lesions1mm 75 lesions2mm 10 lesionsgt2 2 (3mm) lesionsCoalescent 1 (4mm)
lesions R
Left Lung Right Lung
11
112
869
29
34
N
M
L
NO
Q
Qx Group05mm 1 lesion
05mm 5 lesions1mm 4 lesions2mm 1 lesion
05mm 5 lesions1mm 5 lesions2mm 1 lesion
05mm 1 lesion
1mm 1 lesion
05mm 8 lesions1mm 38 lesions2mm 2 lesionsgt2 3 (3mm) 1 (5mm)
1(6mm) lesionsCoalescent 1 (5mm) lesion
M
P
Left Lung Right Lung
1
54
1
11
10
1
R
L
NOR
Q
P
RUTI Group05mm 1 lesion
05mm 3 lesions1mm 3 lesions
05mm 1 lesion1mm 2 lesions
gt2mm 1 (3mm) lesion
05mm 6 lesions1mm 20 lesions2mm 8 lesionsgt2 2 (3mm) 1 (4mm)
lesions
M
Left Lung Right Lung
35 3
6
11
05mm 1mm 2mm gt2 Coalescent
Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
INH x 4weeksbull reduced granulomabull Reduced dissemination of infectionbull Retarded evolution of granulomabullDid not induce TB specific immunity
INH x 4wks + RUTI x 2bull reduced granulomabullReduced dissemination of infectionbull Promoted evolution of granulomabull Induced TB specific immunity
(Gill O PLoS ONE 5(4) e10030 doi101371journalpone0010030)
Conclusion
bull HIV associated TB accounts for the vast majority of TB in sub-Saharan Africa
bull Need new safe short effective regimens for HIV associated TB including MXDR TB
bull Use of adjunctive immunotherapy should be evaluated
bull Need new safe short effective regimens for treating LTBI particularly for DR TB
bull Therapeutic TB vaccines required
Acknowledgements
bull Helen McIlleronbull Ann Ginsburg
- Issues in TB Drug DevelopmentTBHIV
- Presentation outline
- SA has one of the worst TB epidemics in the world
- Integrated TB and HIV treatment saves lives
- Projected use of PI-based ART
- Slide Number 6
- Effect of IPT and ART on TB incidence and mortality
- Effect of IPT and ART on TB incidence and mortality
- Reduction in TB incidence with 36 vs 6 months IPT
- Reduction in TB incidence with 36 vs 6 months IPT
- New drugs amp regimens required for HIV associated TB
- Rifapentine ndash food interactions
- Potential interactions bw fluroquinolones and antiretrovirals
- PXR regulates drug-metabolizing enzymes
- Rifampicin is a potent activator of PXR
- Drug-Drug Interactions
- Combined toxicities
- Role of adjunctive immunotherapy
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
- Supplementing effector cytokines to assist with antimicrobial activity
- Preventing HIV associated TB
- Isoniazid preventive therapy
- Slide Number 25
- LTBI with MDRXDR TB
- Slide Number 27
- Treatment of LTBI
- Slide Number 29
- Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
- Conclusion
- Acknowledgements
-
Author Location Intentionto treat
PerProtocol
Martinson Soweto 19 69
Samandari BotswanaAll 54 65TST+ 93TST- 19
(Martinson et al Union conference 2008 CROI 2009)(Samandari et al Union Conference 2009)
Reduction in TB incidence with 36 vs 6 months IPT
New drugs amp regimens required for HIV associated TB
bull To increase ndash Efficacyndash Safety ndash tolerability
bull To decrease ndash treatment durationndash Complexityndash drug-drug interactions ndash cost
Rifapentine ndash food interactions
0
5
10
15
20
25
30
0 10 20 30 40 50 60
RFP
pla
sma
conc
(m
gL)
Time after dose (h)
0
2
4
6
8
10
12
14
0 10 20 30 40 50 60
25-D
RFP
pla
sma
conc
(m
gL)
Time after dose (h)
High fat meal
Bulk_Low fat meal
Bulk_High fat
Chicken soup
Fasted state
Zvada SP Antimicrob Agents Chemother 2010 54(8)3390-4
+86 (RSE=20)
Potential interactions bw fluroquinolones and antiretrovirals
bullSafety interactionsndash QT prolongation (LPVr)ndash Dysglycaemia (PIs)
bullPK interactionsndash chelation by multivalent anions (buffered ddI)ndash moxifloxacin is a UGT SGT substrate
Antimicrob Agents Chemother 2007 512861ndash6 and 2008 524037-42 J Antimicrob Chemother 2007 601398-401 Clin Infect Dis 2007 451001ndash7 J Int AIDS Soc 2008 11 S95 (abstr) J Infect
2008 57 78-81
CYP2B6
CYP2C9CYP2C8
CYP2B9
CYP3A4CYP3A7
UGTs
GSTs
SULTs
PXR
APBL
PXR regulates drug-metabolizing enzymes
MRP2
OATP2
MDR1PHASE II
PHASE IEFFLUX
TRANSPORTERS
INFLUX
BASELINE ACTIVITYPXR expressionenzymes activityamp transporters
(Pharmacogenomics 2008 9 1695ndash1709 Drug Metab Dispos 2006 101756-63 amp 2007 351400-7)
OATP1B1
Rifampicin is a potent activator of PXR
CYP2B6
CYP2C9CYP2C8
CYP2B9
CYP3A4
UGTs
GSTs
SULTs
PXR-RXR
APBL
MRP2
OATP2
MDR1
Activating ligands trigger altered expression of multiple of enzymes and transporters with
compound effects on substrate concentrations
DRUG
RIF
OATP1B1
CYP3A7
J Pharmacol Exp Ther 2003 304 223-28
Drug InteractionsDiarylquinolines(TMC207)
bullCYP 3A4 SubstratebullNo PK interactions with HZbullPK studies with EFV NVP LPVr awaited
Ethylene Diamines (SQ-109)
CYP 2D6 CYP 2C19 substrate
Nitroimidazoles (PA-824 OPC-67683)
Not metabolized by or interfere with CYP enzymes
oxazolidinones (PNU-100480 Linezolid )
Mono Aminine Oxidase InhibitorsNot metabolized by or interfere with drug metabolizing enzymes
Drug-Drug Interactions
(Source H McIlleron)
Combined toxicities
Example of Linezolidbull CNS toxicity EFVbull Peripheral neuropathy DDI D4Tbull Lactic acidosis D4Tbull Myelosuppression ZDV
(Source H McIlleron)
Role of adjunctive immunotherapy
bull Shortening the duration of TB treatment bull Improve treatment success of M(X)DR TBbull Reduce clinical complicationsbull Reduce rate of recurrent TB
Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
GMP manufacturing capacity existsIvIgHE2000 M vaccaeanti-IL-4 RUTI
GMP capacity to be establishedhsp65 DNA vaccine
OtherDzherelo
Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
GMP manufacturing capacity existsIvIgHE2000 M vaccaeanti-IL-4 RUTI
GMP capacity to be establishedhsp65 DNA vaccine
OtherDzherelo
bull Thalidomide analogsndash Inhibit TNFα which is essential for granuloma
formationbull Entanercept (soluble TNF receptor)bull High dose prednisone
Concernsbull Requires concomitant bactericidal therapybull Agents inhibit protective immunity thereby
facilitating growth of organismsbull immunosuppression may result in OIs
Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
Supplementing effector cytokines to assist with antimicrobial activityRh-IFN-γ amp αRh-IL-2Rh-GM-CSFIL-12
Preventing HIV associated TB
Latent TB infection
TB disease
Treatment of latent TB infection
bull Isoniazid preventive therapy
Restore boost protective immunitybull ARTbull PrePost exposure TB vaccines
Isoniazid preventive therapy
bull Good safety profilebull Effective cheap amp readily availablebull Public health benefitBUTbull Requires a long treatment periodbull TB rates remain high in pts with advanced
HIV diseasebull Limited durabilitybull Adherence problematicbull Concern about promoting resistance
bull Efficacy compared to INH
TB incidence rate ratio (RR)minus INH (13) RR = 067minus INH + RIF (2) RR = 041minus RIF + PZA (4) RR = 054minus INH RIF + PZA (1) RR = 048
bull Increased side effects resulting in discontinuation
Multi-drug TB preventive therapyregimens
LTBI with MDRXDR TB
bull MDR TB increased globallybull Close contacts of MDRXDR TB patients are
at increased risk of becoming infectedbull PLHIV infected with MDRXDR TB are at
high risk of progressing to diseasebull Almost no data and inconsistent
international guidelines for treating contacts of MDR TB patients
HIV associated MDR amp XDR TB in SA
(N Gandhi Am J Resp Crit Care Med 2009)
Treatment of LTBIbull Effective tolerable ultra short course
treatment for DS LTBI requiredndash Mouse model of LTBI
(Eric Nuermberger) bull JgtRgtRHbull J=P=HPbull JPgtPZ
bull Effective treatment for LTBI with MDRXDR TB urgently neededndash need to evaluate regimens in mouse model
0003
006009
0003
006009
01
10
100
1000
10000
New TB cases
million in 2050
Treatment ratelatentyr
Vaccinations uninfected yr
ELIMINATING TB BY 2050BY PREVENTING INFECTION AND TREATING LATENT
INFECTIONEliminating TB by 2050Requires both PT and vaccines
M
8
L
O
Q
P
Control Group05mm 3 lesions1mm 25 lesions2mm 6 lesions
05mm 18 lesions1mm 8 lesions2mm 3 lesions
05mm 53 lesions1mm 13 lesions2mm 3 lesions
05mm 4 lesions1mm 1 lesions2mm 3 lesions
05mm 4 lesions1mm 3 lesions2mm 1 lesion
05mm 7 lesions1mm 4 lesions
05mm 24 lesions1mm 75 lesions2mm 10 lesionsgt2 2 (3mm) lesionsCoalescent 1 (4mm)
lesions R
Left Lung Right Lung
11
112
869
29
34
N
M
L
NO
Q
Qx Group05mm 1 lesion
05mm 5 lesions1mm 4 lesions2mm 1 lesion
05mm 5 lesions1mm 5 lesions2mm 1 lesion
05mm 1 lesion
1mm 1 lesion
05mm 8 lesions1mm 38 lesions2mm 2 lesionsgt2 3 (3mm) 1 (5mm)
1(6mm) lesionsCoalescent 1 (5mm) lesion
M
P
Left Lung Right Lung
1
54
1
11
10
1
R
L
NOR
Q
P
RUTI Group05mm 1 lesion
05mm 3 lesions1mm 3 lesions
05mm 1 lesion1mm 2 lesions
gt2mm 1 (3mm) lesion
05mm 6 lesions1mm 20 lesions2mm 8 lesionsgt2 2 (3mm) 1 (4mm)
lesions
M
Left Lung Right Lung
35 3
6
11
05mm 1mm 2mm gt2 Coalescent
Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
INH x 4weeksbull reduced granulomabull Reduced dissemination of infectionbull Retarded evolution of granulomabullDid not induce TB specific immunity
INH x 4wks + RUTI x 2bull reduced granulomabullReduced dissemination of infectionbull Promoted evolution of granulomabull Induced TB specific immunity
(Gill O PLoS ONE 5(4) e10030 doi101371journalpone0010030)
Conclusion
bull HIV associated TB accounts for the vast majority of TB in sub-Saharan Africa
bull Need new safe short effective regimens for HIV associated TB including MXDR TB
bull Use of adjunctive immunotherapy should be evaluated
bull Need new safe short effective regimens for treating LTBI particularly for DR TB
bull Therapeutic TB vaccines required
Acknowledgements
bull Helen McIlleronbull Ann Ginsburg
- Issues in TB Drug DevelopmentTBHIV
- Presentation outline
- SA has one of the worst TB epidemics in the world
- Integrated TB and HIV treatment saves lives
- Projected use of PI-based ART
- Slide Number 6
- Effect of IPT and ART on TB incidence and mortality
- Effect of IPT and ART on TB incidence and mortality
- Reduction in TB incidence with 36 vs 6 months IPT
- Reduction in TB incidence with 36 vs 6 months IPT
- New drugs amp regimens required for HIV associated TB
- Rifapentine ndash food interactions
- Potential interactions bw fluroquinolones and antiretrovirals
- PXR regulates drug-metabolizing enzymes
- Rifampicin is a potent activator of PXR
- Drug-Drug Interactions
- Combined toxicities
- Role of adjunctive immunotherapy
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
- Supplementing effector cytokines to assist with antimicrobial activity
- Preventing HIV associated TB
- Isoniazid preventive therapy
- Slide Number 25
- LTBI with MDRXDR TB
- Slide Number 27
- Treatment of LTBI
- Slide Number 29
- Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
- Conclusion
- Acknowledgements
-
New drugs amp regimens required for HIV associated TB
bull To increase ndash Efficacyndash Safety ndash tolerability
bull To decrease ndash treatment durationndash Complexityndash drug-drug interactions ndash cost
Rifapentine ndash food interactions
0
5
10
15
20
25
30
0 10 20 30 40 50 60
RFP
pla
sma
conc
(m
gL)
Time after dose (h)
0
2
4
6
8
10
12
14
0 10 20 30 40 50 60
25-D
RFP
pla
sma
conc
(m
gL)
Time after dose (h)
High fat meal
Bulk_Low fat meal
Bulk_High fat
Chicken soup
Fasted state
Zvada SP Antimicrob Agents Chemother 2010 54(8)3390-4
+86 (RSE=20)
Potential interactions bw fluroquinolones and antiretrovirals
bullSafety interactionsndash QT prolongation (LPVr)ndash Dysglycaemia (PIs)
bullPK interactionsndash chelation by multivalent anions (buffered ddI)ndash moxifloxacin is a UGT SGT substrate
Antimicrob Agents Chemother 2007 512861ndash6 and 2008 524037-42 J Antimicrob Chemother 2007 601398-401 Clin Infect Dis 2007 451001ndash7 J Int AIDS Soc 2008 11 S95 (abstr) J Infect
2008 57 78-81
CYP2B6
CYP2C9CYP2C8
CYP2B9
CYP3A4CYP3A7
UGTs
GSTs
SULTs
PXR
APBL
PXR regulates drug-metabolizing enzymes
MRP2
OATP2
MDR1PHASE II
PHASE IEFFLUX
TRANSPORTERS
INFLUX
BASELINE ACTIVITYPXR expressionenzymes activityamp transporters
(Pharmacogenomics 2008 9 1695ndash1709 Drug Metab Dispos 2006 101756-63 amp 2007 351400-7)
OATP1B1
Rifampicin is a potent activator of PXR
CYP2B6
CYP2C9CYP2C8
CYP2B9
CYP3A4
UGTs
GSTs
SULTs
PXR-RXR
APBL
MRP2
OATP2
MDR1
Activating ligands trigger altered expression of multiple of enzymes and transporters with
compound effects on substrate concentrations
DRUG
RIF
OATP1B1
CYP3A7
J Pharmacol Exp Ther 2003 304 223-28
Drug InteractionsDiarylquinolines(TMC207)
bullCYP 3A4 SubstratebullNo PK interactions with HZbullPK studies with EFV NVP LPVr awaited
Ethylene Diamines (SQ-109)
CYP 2D6 CYP 2C19 substrate
Nitroimidazoles (PA-824 OPC-67683)
Not metabolized by or interfere with CYP enzymes
oxazolidinones (PNU-100480 Linezolid )
Mono Aminine Oxidase InhibitorsNot metabolized by or interfere with drug metabolizing enzymes
Drug-Drug Interactions
(Source H McIlleron)
Combined toxicities
Example of Linezolidbull CNS toxicity EFVbull Peripheral neuropathy DDI D4Tbull Lactic acidosis D4Tbull Myelosuppression ZDV
(Source H McIlleron)
Role of adjunctive immunotherapy
bull Shortening the duration of TB treatment bull Improve treatment success of M(X)DR TBbull Reduce clinical complicationsbull Reduce rate of recurrent TB
Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
GMP manufacturing capacity existsIvIgHE2000 M vaccaeanti-IL-4 RUTI
GMP capacity to be establishedhsp65 DNA vaccine
OtherDzherelo
Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
GMP manufacturing capacity existsIvIgHE2000 M vaccaeanti-IL-4 RUTI
GMP capacity to be establishedhsp65 DNA vaccine
OtherDzherelo
bull Thalidomide analogsndash Inhibit TNFα which is essential for granuloma
formationbull Entanercept (soluble TNF receptor)bull High dose prednisone
Concernsbull Requires concomitant bactericidal therapybull Agents inhibit protective immunity thereby
facilitating growth of organismsbull immunosuppression may result in OIs
Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
Supplementing effector cytokines to assist with antimicrobial activityRh-IFN-γ amp αRh-IL-2Rh-GM-CSFIL-12
Preventing HIV associated TB
Latent TB infection
TB disease
Treatment of latent TB infection
bull Isoniazid preventive therapy
Restore boost protective immunitybull ARTbull PrePost exposure TB vaccines
Isoniazid preventive therapy
bull Good safety profilebull Effective cheap amp readily availablebull Public health benefitBUTbull Requires a long treatment periodbull TB rates remain high in pts with advanced
HIV diseasebull Limited durabilitybull Adherence problematicbull Concern about promoting resistance
bull Efficacy compared to INH
TB incidence rate ratio (RR)minus INH (13) RR = 067minus INH + RIF (2) RR = 041minus RIF + PZA (4) RR = 054minus INH RIF + PZA (1) RR = 048
bull Increased side effects resulting in discontinuation
Multi-drug TB preventive therapyregimens
LTBI with MDRXDR TB
bull MDR TB increased globallybull Close contacts of MDRXDR TB patients are
at increased risk of becoming infectedbull PLHIV infected with MDRXDR TB are at
high risk of progressing to diseasebull Almost no data and inconsistent
international guidelines for treating contacts of MDR TB patients
HIV associated MDR amp XDR TB in SA
(N Gandhi Am J Resp Crit Care Med 2009)
Treatment of LTBIbull Effective tolerable ultra short course
treatment for DS LTBI requiredndash Mouse model of LTBI
(Eric Nuermberger) bull JgtRgtRHbull J=P=HPbull JPgtPZ
bull Effective treatment for LTBI with MDRXDR TB urgently neededndash need to evaluate regimens in mouse model
0003
006009
0003
006009
01
10
100
1000
10000
New TB cases
million in 2050
Treatment ratelatentyr
Vaccinations uninfected yr
ELIMINATING TB BY 2050BY PREVENTING INFECTION AND TREATING LATENT
INFECTIONEliminating TB by 2050Requires both PT and vaccines
M
8
L
O
Q
P
Control Group05mm 3 lesions1mm 25 lesions2mm 6 lesions
05mm 18 lesions1mm 8 lesions2mm 3 lesions
05mm 53 lesions1mm 13 lesions2mm 3 lesions
05mm 4 lesions1mm 1 lesions2mm 3 lesions
05mm 4 lesions1mm 3 lesions2mm 1 lesion
05mm 7 lesions1mm 4 lesions
05mm 24 lesions1mm 75 lesions2mm 10 lesionsgt2 2 (3mm) lesionsCoalescent 1 (4mm)
lesions R
Left Lung Right Lung
11
112
869
29
34
N
M
L
NO
Q
Qx Group05mm 1 lesion
05mm 5 lesions1mm 4 lesions2mm 1 lesion
05mm 5 lesions1mm 5 lesions2mm 1 lesion
05mm 1 lesion
1mm 1 lesion
05mm 8 lesions1mm 38 lesions2mm 2 lesionsgt2 3 (3mm) 1 (5mm)
1(6mm) lesionsCoalescent 1 (5mm) lesion
M
P
Left Lung Right Lung
1
54
1
11
10
1
R
L
NOR
Q
P
RUTI Group05mm 1 lesion
05mm 3 lesions1mm 3 lesions
05mm 1 lesion1mm 2 lesions
gt2mm 1 (3mm) lesion
05mm 6 lesions1mm 20 lesions2mm 8 lesionsgt2 2 (3mm) 1 (4mm)
lesions
M
Left Lung Right Lung
35 3
6
11
05mm 1mm 2mm gt2 Coalescent
Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
INH x 4weeksbull reduced granulomabull Reduced dissemination of infectionbull Retarded evolution of granulomabullDid not induce TB specific immunity
INH x 4wks + RUTI x 2bull reduced granulomabullReduced dissemination of infectionbull Promoted evolution of granulomabull Induced TB specific immunity
(Gill O PLoS ONE 5(4) e10030 doi101371journalpone0010030)
Conclusion
bull HIV associated TB accounts for the vast majority of TB in sub-Saharan Africa
bull Need new safe short effective regimens for HIV associated TB including MXDR TB
bull Use of adjunctive immunotherapy should be evaluated
bull Need new safe short effective regimens for treating LTBI particularly for DR TB
bull Therapeutic TB vaccines required
Acknowledgements
bull Helen McIlleronbull Ann Ginsburg
- Issues in TB Drug DevelopmentTBHIV
- Presentation outline
- SA has one of the worst TB epidemics in the world
- Integrated TB and HIV treatment saves lives
- Projected use of PI-based ART
- Slide Number 6
- Effect of IPT and ART on TB incidence and mortality
- Effect of IPT and ART on TB incidence and mortality
- Reduction in TB incidence with 36 vs 6 months IPT
- Reduction in TB incidence with 36 vs 6 months IPT
- New drugs amp regimens required for HIV associated TB
- Rifapentine ndash food interactions
- Potential interactions bw fluroquinolones and antiretrovirals
- PXR regulates drug-metabolizing enzymes
- Rifampicin is a potent activator of PXR
- Drug-Drug Interactions
- Combined toxicities
- Role of adjunctive immunotherapy
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
- Supplementing effector cytokines to assist with antimicrobial activity
- Preventing HIV associated TB
- Isoniazid preventive therapy
- Slide Number 25
- LTBI with MDRXDR TB
- Slide Number 27
- Treatment of LTBI
- Slide Number 29
- Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
- Conclusion
- Acknowledgements
-
Rifapentine ndash food interactions
0
5
10
15
20
25
30
0 10 20 30 40 50 60
RFP
pla
sma
conc
(m
gL)
Time after dose (h)
0
2
4
6
8
10
12
14
0 10 20 30 40 50 60
25-D
RFP
pla
sma
conc
(m
gL)
Time after dose (h)
High fat meal
Bulk_Low fat meal
Bulk_High fat
Chicken soup
Fasted state
Zvada SP Antimicrob Agents Chemother 2010 54(8)3390-4
+86 (RSE=20)
Potential interactions bw fluroquinolones and antiretrovirals
bullSafety interactionsndash QT prolongation (LPVr)ndash Dysglycaemia (PIs)
bullPK interactionsndash chelation by multivalent anions (buffered ddI)ndash moxifloxacin is a UGT SGT substrate
Antimicrob Agents Chemother 2007 512861ndash6 and 2008 524037-42 J Antimicrob Chemother 2007 601398-401 Clin Infect Dis 2007 451001ndash7 J Int AIDS Soc 2008 11 S95 (abstr) J Infect
2008 57 78-81
CYP2B6
CYP2C9CYP2C8
CYP2B9
CYP3A4CYP3A7
UGTs
GSTs
SULTs
PXR
APBL
PXR regulates drug-metabolizing enzymes
MRP2
OATP2
MDR1PHASE II
PHASE IEFFLUX
TRANSPORTERS
INFLUX
BASELINE ACTIVITYPXR expressionenzymes activityamp transporters
(Pharmacogenomics 2008 9 1695ndash1709 Drug Metab Dispos 2006 101756-63 amp 2007 351400-7)
OATP1B1
Rifampicin is a potent activator of PXR
CYP2B6
CYP2C9CYP2C8
CYP2B9
CYP3A4
UGTs
GSTs
SULTs
PXR-RXR
APBL
MRP2
OATP2
MDR1
Activating ligands trigger altered expression of multiple of enzymes and transporters with
compound effects on substrate concentrations
DRUG
RIF
OATP1B1
CYP3A7
J Pharmacol Exp Ther 2003 304 223-28
Drug InteractionsDiarylquinolines(TMC207)
bullCYP 3A4 SubstratebullNo PK interactions with HZbullPK studies with EFV NVP LPVr awaited
Ethylene Diamines (SQ-109)
CYP 2D6 CYP 2C19 substrate
Nitroimidazoles (PA-824 OPC-67683)
Not metabolized by or interfere with CYP enzymes
oxazolidinones (PNU-100480 Linezolid )
Mono Aminine Oxidase InhibitorsNot metabolized by or interfere with drug metabolizing enzymes
Drug-Drug Interactions
(Source H McIlleron)
Combined toxicities
Example of Linezolidbull CNS toxicity EFVbull Peripheral neuropathy DDI D4Tbull Lactic acidosis D4Tbull Myelosuppression ZDV
(Source H McIlleron)
Role of adjunctive immunotherapy
bull Shortening the duration of TB treatment bull Improve treatment success of M(X)DR TBbull Reduce clinical complicationsbull Reduce rate of recurrent TB
Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
GMP manufacturing capacity existsIvIgHE2000 M vaccaeanti-IL-4 RUTI
GMP capacity to be establishedhsp65 DNA vaccine
OtherDzherelo
Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
GMP manufacturing capacity existsIvIgHE2000 M vaccaeanti-IL-4 RUTI
GMP capacity to be establishedhsp65 DNA vaccine
OtherDzherelo
bull Thalidomide analogsndash Inhibit TNFα which is essential for granuloma
formationbull Entanercept (soluble TNF receptor)bull High dose prednisone
Concernsbull Requires concomitant bactericidal therapybull Agents inhibit protective immunity thereby
facilitating growth of organismsbull immunosuppression may result in OIs
Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
Supplementing effector cytokines to assist with antimicrobial activityRh-IFN-γ amp αRh-IL-2Rh-GM-CSFIL-12
Preventing HIV associated TB
Latent TB infection
TB disease
Treatment of latent TB infection
bull Isoniazid preventive therapy
Restore boost protective immunitybull ARTbull PrePost exposure TB vaccines
Isoniazid preventive therapy
bull Good safety profilebull Effective cheap amp readily availablebull Public health benefitBUTbull Requires a long treatment periodbull TB rates remain high in pts with advanced
HIV diseasebull Limited durabilitybull Adherence problematicbull Concern about promoting resistance
bull Efficacy compared to INH
TB incidence rate ratio (RR)minus INH (13) RR = 067minus INH + RIF (2) RR = 041minus RIF + PZA (4) RR = 054minus INH RIF + PZA (1) RR = 048
bull Increased side effects resulting in discontinuation
Multi-drug TB preventive therapyregimens
LTBI with MDRXDR TB
bull MDR TB increased globallybull Close contacts of MDRXDR TB patients are
at increased risk of becoming infectedbull PLHIV infected with MDRXDR TB are at
high risk of progressing to diseasebull Almost no data and inconsistent
international guidelines for treating contacts of MDR TB patients
HIV associated MDR amp XDR TB in SA
(N Gandhi Am J Resp Crit Care Med 2009)
Treatment of LTBIbull Effective tolerable ultra short course
treatment for DS LTBI requiredndash Mouse model of LTBI
(Eric Nuermberger) bull JgtRgtRHbull J=P=HPbull JPgtPZ
bull Effective treatment for LTBI with MDRXDR TB urgently neededndash need to evaluate regimens in mouse model
0003
006009
0003
006009
01
10
100
1000
10000
New TB cases
million in 2050
Treatment ratelatentyr
Vaccinations uninfected yr
ELIMINATING TB BY 2050BY PREVENTING INFECTION AND TREATING LATENT
INFECTIONEliminating TB by 2050Requires both PT and vaccines
M
8
L
O
Q
P
Control Group05mm 3 lesions1mm 25 lesions2mm 6 lesions
05mm 18 lesions1mm 8 lesions2mm 3 lesions
05mm 53 lesions1mm 13 lesions2mm 3 lesions
05mm 4 lesions1mm 1 lesions2mm 3 lesions
05mm 4 lesions1mm 3 lesions2mm 1 lesion
05mm 7 lesions1mm 4 lesions
05mm 24 lesions1mm 75 lesions2mm 10 lesionsgt2 2 (3mm) lesionsCoalescent 1 (4mm)
lesions R
Left Lung Right Lung
11
112
869
29
34
N
M
L
NO
Q
Qx Group05mm 1 lesion
05mm 5 lesions1mm 4 lesions2mm 1 lesion
05mm 5 lesions1mm 5 lesions2mm 1 lesion
05mm 1 lesion
1mm 1 lesion
05mm 8 lesions1mm 38 lesions2mm 2 lesionsgt2 3 (3mm) 1 (5mm)
1(6mm) lesionsCoalescent 1 (5mm) lesion
M
P
Left Lung Right Lung
1
54
1
11
10
1
R
L
NOR
Q
P
RUTI Group05mm 1 lesion
05mm 3 lesions1mm 3 lesions
05mm 1 lesion1mm 2 lesions
gt2mm 1 (3mm) lesion
05mm 6 lesions1mm 20 lesions2mm 8 lesionsgt2 2 (3mm) 1 (4mm)
lesions
M
Left Lung Right Lung
35 3
6
11
05mm 1mm 2mm gt2 Coalescent
Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
INH x 4weeksbull reduced granulomabull Reduced dissemination of infectionbull Retarded evolution of granulomabullDid not induce TB specific immunity
INH x 4wks + RUTI x 2bull reduced granulomabullReduced dissemination of infectionbull Promoted evolution of granulomabull Induced TB specific immunity
(Gill O PLoS ONE 5(4) e10030 doi101371journalpone0010030)
Conclusion
bull HIV associated TB accounts for the vast majority of TB in sub-Saharan Africa
bull Need new safe short effective regimens for HIV associated TB including MXDR TB
bull Use of adjunctive immunotherapy should be evaluated
bull Need new safe short effective regimens for treating LTBI particularly for DR TB
bull Therapeutic TB vaccines required
Acknowledgements
bull Helen McIlleronbull Ann Ginsburg
- Issues in TB Drug DevelopmentTBHIV
- Presentation outline
- SA has one of the worst TB epidemics in the world
- Integrated TB and HIV treatment saves lives
- Projected use of PI-based ART
- Slide Number 6
- Effect of IPT and ART on TB incidence and mortality
- Effect of IPT and ART on TB incidence and mortality
- Reduction in TB incidence with 36 vs 6 months IPT
- Reduction in TB incidence with 36 vs 6 months IPT
- New drugs amp regimens required for HIV associated TB
- Rifapentine ndash food interactions
- Potential interactions bw fluroquinolones and antiretrovirals
- PXR regulates drug-metabolizing enzymes
- Rifampicin is a potent activator of PXR
- Drug-Drug Interactions
- Combined toxicities
- Role of adjunctive immunotherapy
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
- Supplementing effector cytokines to assist with antimicrobial activity
- Preventing HIV associated TB
- Isoniazid preventive therapy
- Slide Number 25
- LTBI with MDRXDR TB
- Slide Number 27
- Treatment of LTBI
- Slide Number 29
- Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
- Conclusion
- Acknowledgements
-
Potential interactions bw fluroquinolones and antiretrovirals
bullSafety interactionsndash QT prolongation (LPVr)ndash Dysglycaemia (PIs)
bullPK interactionsndash chelation by multivalent anions (buffered ddI)ndash moxifloxacin is a UGT SGT substrate
Antimicrob Agents Chemother 2007 512861ndash6 and 2008 524037-42 J Antimicrob Chemother 2007 601398-401 Clin Infect Dis 2007 451001ndash7 J Int AIDS Soc 2008 11 S95 (abstr) J Infect
2008 57 78-81
CYP2B6
CYP2C9CYP2C8
CYP2B9
CYP3A4CYP3A7
UGTs
GSTs
SULTs
PXR
APBL
PXR regulates drug-metabolizing enzymes
MRP2
OATP2
MDR1PHASE II
PHASE IEFFLUX
TRANSPORTERS
INFLUX
BASELINE ACTIVITYPXR expressionenzymes activityamp transporters
(Pharmacogenomics 2008 9 1695ndash1709 Drug Metab Dispos 2006 101756-63 amp 2007 351400-7)
OATP1B1
Rifampicin is a potent activator of PXR
CYP2B6
CYP2C9CYP2C8
CYP2B9
CYP3A4
UGTs
GSTs
SULTs
PXR-RXR
APBL
MRP2
OATP2
MDR1
Activating ligands trigger altered expression of multiple of enzymes and transporters with
compound effects on substrate concentrations
DRUG
RIF
OATP1B1
CYP3A7
J Pharmacol Exp Ther 2003 304 223-28
Drug InteractionsDiarylquinolines(TMC207)
bullCYP 3A4 SubstratebullNo PK interactions with HZbullPK studies with EFV NVP LPVr awaited
Ethylene Diamines (SQ-109)
CYP 2D6 CYP 2C19 substrate
Nitroimidazoles (PA-824 OPC-67683)
Not metabolized by or interfere with CYP enzymes
oxazolidinones (PNU-100480 Linezolid )
Mono Aminine Oxidase InhibitorsNot metabolized by or interfere with drug metabolizing enzymes
Drug-Drug Interactions
(Source H McIlleron)
Combined toxicities
Example of Linezolidbull CNS toxicity EFVbull Peripheral neuropathy DDI D4Tbull Lactic acidosis D4Tbull Myelosuppression ZDV
(Source H McIlleron)
Role of adjunctive immunotherapy
bull Shortening the duration of TB treatment bull Improve treatment success of M(X)DR TBbull Reduce clinical complicationsbull Reduce rate of recurrent TB
Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
GMP manufacturing capacity existsIvIgHE2000 M vaccaeanti-IL-4 RUTI
GMP capacity to be establishedhsp65 DNA vaccine
OtherDzherelo
Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
GMP manufacturing capacity existsIvIgHE2000 M vaccaeanti-IL-4 RUTI
GMP capacity to be establishedhsp65 DNA vaccine
OtherDzherelo
bull Thalidomide analogsndash Inhibit TNFα which is essential for granuloma
formationbull Entanercept (soluble TNF receptor)bull High dose prednisone
Concernsbull Requires concomitant bactericidal therapybull Agents inhibit protective immunity thereby
facilitating growth of organismsbull immunosuppression may result in OIs
Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
Supplementing effector cytokines to assist with antimicrobial activityRh-IFN-γ amp αRh-IL-2Rh-GM-CSFIL-12
Preventing HIV associated TB
Latent TB infection
TB disease
Treatment of latent TB infection
bull Isoniazid preventive therapy
Restore boost protective immunitybull ARTbull PrePost exposure TB vaccines
Isoniazid preventive therapy
bull Good safety profilebull Effective cheap amp readily availablebull Public health benefitBUTbull Requires a long treatment periodbull TB rates remain high in pts with advanced
HIV diseasebull Limited durabilitybull Adherence problematicbull Concern about promoting resistance
bull Efficacy compared to INH
TB incidence rate ratio (RR)minus INH (13) RR = 067minus INH + RIF (2) RR = 041minus RIF + PZA (4) RR = 054minus INH RIF + PZA (1) RR = 048
bull Increased side effects resulting in discontinuation
Multi-drug TB preventive therapyregimens
LTBI with MDRXDR TB
bull MDR TB increased globallybull Close contacts of MDRXDR TB patients are
at increased risk of becoming infectedbull PLHIV infected with MDRXDR TB are at
high risk of progressing to diseasebull Almost no data and inconsistent
international guidelines for treating contacts of MDR TB patients
HIV associated MDR amp XDR TB in SA
(N Gandhi Am J Resp Crit Care Med 2009)
Treatment of LTBIbull Effective tolerable ultra short course
treatment for DS LTBI requiredndash Mouse model of LTBI
(Eric Nuermberger) bull JgtRgtRHbull J=P=HPbull JPgtPZ
bull Effective treatment for LTBI with MDRXDR TB urgently neededndash need to evaluate regimens in mouse model
0003
006009
0003
006009
01
10
100
1000
10000
New TB cases
million in 2050
Treatment ratelatentyr
Vaccinations uninfected yr
ELIMINATING TB BY 2050BY PREVENTING INFECTION AND TREATING LATENT
INFECTIONEliminating TB by 2050Requires both PT and vaccines
M
8
L
O
Q
P
Control Group05mm 3 lesions1mm 25 lesions2mm 6 lesions
05mm 18 lesions1mm 8 lesions2mm 3 lesions
05mm 53 lesions1mm 13 lesions2mm 3 lesions
05mm 4 lesions1mm 1 lesions2mm 3 lesions
05mm 4 lesions1mm 3 lesions2mm 1 lesion
05mm 7 lesions1mm 4 lesions
05mm 24 lesions1mm 75 lesions2mm 10 lesionsgt2 2 (3mm) lesionsCoalescent 1 (4mm)
lesions R
Left Lung Right Lung
11
112
869
29
34
N
M
L
NO
Q
Qx Group05mm 1 lesion
05mm 5 lesions1mm 4 lesions2mm 1 lesion
05mm 5 lesions1mm 5 lesions2mm 1 lesion
05mm 1 lesion
1mm 1 lesion
05mm 8 lesions1mm 38 lesions2mm 2 lesionsgt2 3 (3mm) 1 (5mm)
1(6mm) lesionsCoalescent 1 (5mm) lesion
M
P
Left Lung Right Lung
1
54
1
11
10
1
R
L
NOR
Q
P
RUTI Group05mm 1 lesion
05mm 3 lesions1mm 3 lesions
05mm 1 lesion1mm 2 lesions
gt2mm 1 (3mm) lesion
05mm 6 lesions1mm 20 lesions2mm 8 lesionsgt2 2 (3mm) 1 (4mm)
lesions
M
Left Lung Right Lung
35 3
6
11
05mm 1mm 2mm gt2 Coalescent
Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
INH x 4weeksbull reduced granulomabull Reduced dissemination of infectionbull Retarded evolution of granulomabullDid not induce TB specific immunity
INH x 4wks + RUTI x 2bull reduced granulomabullReduced dissemination of infectionbull Promoted evolution of granulomabull Induced TB specific immunity
(Gill O PLoS ONE 5(4) e10030 doi101371journalpone0010030)
Conclusion
bull HIV associated TB accounts for the vast majority of TB in sub-Saharan Africa
bull Need new safe short effective regimens for HIV associated TB including MXDR TB
bull Use of adjunctive immunotherapy should be evaluated
bull Need new safe short effective regimens for treating LTBI particularly for DR TB
bull Therapeutic TB vaccines required
Acknowledgements
bull Helen McIlleronbull Ann Ginsburg
- Issues in TB Drug DevelopmentTBHIV
- Presentation outline
- SA has one of the worst TB epidemics in the world
- Integrated TB and HIV treatment saves lives
- Projected use of PI-based ART
- Slide Number 6
- Effect of IPT and ART on TB incidence and mortality
- Effect of IPT and ART on TB incidence and mortality
- Reduction in TB incidence with 36 vs 6 months IPT
- Reduction in TB incidence with 36 vs 6 months IPT
- New drugs amp regimens required for HIV associated TB
- Rifapentine ndash food interactions
- Potential interactions bw fluroquinolones and antiretrovirals
- PXR regulates drug-metabolizing enzymes
- Rifampicin is a potent activator of PXR
- Drug-Drug Interactions
- Combined toxicities
- Role of adjunctive immunotherapy
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
- Supplementing effector cytokines to assist with antimicrobial activity
- Preventing HIV associated TB
- Isoniazid preventive therapy
- Slide Number 25
- LTBI with MDRXDR TB
- Slide Number 27
- Treatment of LTBI
- Slide Number 29
- Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
- Conclusion
- Acknowledgements
-
CYP2B6
CYP2C9CYP2C8
CYP2B9
CYP3A4CYP3A7
UGTs
GSTs
SULTs
PXR
APBL
PXR regulates drug-metabolizing enzymes
MRP2
OATP2
MDR1PHASE II
PHASE IEFFLUX
TRANSPORTERS
INFLUX
BASELINE ACTIVITYPXR expressionenzymes activityamp transporters
(Pharmacogenomics 2008 9 1695ndash1709 Drug Metab Dispos 2006 101756-63 amp 2007 351400-7)
OATP1B1
Rifampicin is a potent activator of PXR
CYP2B6
CYP2C9CYP2C8
CYP2B9
CYP3A4
UGTs
GSTs
SULTs
PXR-RXR
APBL
MRP2
OATP2
MDR1
Activating ligands trigger altered expression of multiple of enzymes and transporters with
compound effects on substrate concentrations
DRUG
RIF
OATP1B1
CYP3A7
J Pharmacol Exp Ther 2003 304 223-28
Drug InteractionsDiarylquinolines(TMC207)
bullCYP 3A4 SubstratebullNo PK interactions with HZbullPK studies with EFV NVP LPVr awaited
Ethylene Diamines (SQ-109)
CYP 2D6 CYP 2C19 substrate
Nitroimidazoles (PA-824 OPC-67683)
Not metabolized by or interfere with CYP enzymes
oxazolidinones (PNU-100480 Linezolid )
Mono Aminine Oxidase InhibitorsNot metabolized by or interfere with drug metabolizing enzymes
Drug-Drug Interactions
(Source H McIlleron)
Combined toxicities
Example of Linezolidbull CNS toxicity EFVbull Peripheral neuropathy DDI D4Tbull Lactic acidosis D4Tbull Myelosuppression ZDV
(Source H McIlleron)
Role of adjunctive immunotherapy
bull Shortening the duration of TB treatment bull Improve treatment success of M(X)DR TBbull Reduce clinical complicationsbull Reduce rate of recurrent TB
Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
GMP manufacturing capacity existsIvIgHE2000 M vaccaeanti-IL-4 RUTI
GMP capacity to be establishedhsp65 DNA vaccine
OtherDzherelo
Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
GMP manufacturing capacity existsIvIgHE2000 M vaccaeanti-IL-4 RUTI
GMP capacity to be establishedhsp65 DNA vaccine
OtherDzherelo
bull Thalidomide analogsndash Inhibit TNFα which is essential for granuloma
formationbull Entanercept (soluble TNF receptor)bull High dose prednisone
Concernsbull Requires concomitant bactericidal therapybull Agents inhibit protective immunity thereby
facilitating growth of organismsbull immunosuppression may result in OIs
Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
Supplementing effector cytokines to assist with antimicrobial activityRh-IFN-γ amp αRh-IL-2Rh-GM-CSFIL-12
Preventing HIV associated TB
Latent TB infection
TB disease
Treatment of latent TB infection
bull Isoniazid preventive therapy
Restore boost protective immunitybull ARTbull PrePost exposure TB vaccines
Isoniazid preventive therapy
bull Good safety profilebull Effective cheap amp readily availablebull Public health benefitBUTbull Requires a long treatment periodbull TB rates remain high in pts with advanced
HIV diseasebull Limited durabilitybull Adherence problematicbull Concern about promoting resistance
bull Efficacy compared to INH
TB incidence rate ratio (RR)minus INH (13) RR = 067minus INH + RIF (2) RR = 041minus RIF + PZA (4) RR = 054minus INH RIF + PZA (1) RR = 048
bull Increased side effects resulting in discontinuation
Multi-drug TB preventive therapyregimens
LTBI with MDRXDR TB
bull MDR TB increased globallybull Close contacts of MDRXDR TB patients are
at increased risk of becoming infectedbull PLHIV infected with MDRXDR TB are at
high risk of progressing to diseasebull Almost no data and inconsistent
international guidelines for treating contacts of MDR TB patients
HIV associated MDR amp XDR TB in SA
(N Gandhi Am J Resp Crit Care Med 2009)
Treatment of LTBIbull Effective tolerable ultra short course
treatment for DS LTBI requiredndash Mouse model of LTBI
(Eric Nuermberger) bull JgtRgtRHbull J=P=HPbull JPgtPZ
bull Effective treatment for LTBI with MDRXDR TB urgently neededndash need to evaluate regimens in mouse model
0003
006009
0003
006009
01
10
100
1000
10000
New TB cases
million in 2050
Treatment ratelatentyr
Vaccinations uninfected yr
ELIMINATING TB BY 2050BY PREVENTING INFECTION AND TREATING LATENT
INFECTIONEliminating TB by 2050Requires both PT and vaccines
M
8
L
O
Q
P
Control Group05mm 3 lesions1mm 25 lesions2mm 6 lesions
05mm 18 lesions1mm 8 lesions2mm 3 lesions
05mm 53 lesions1mm 13 lesions2mm 3 lesions
05mm 4 lesions1mm 1 lesions2mm 3 lesions
05mm 4 lesions1mm 3 lesions2mm 1 lesion
05mm 7 lesions1mm 4 lesions
05mm 24 lesions1mm 75 lesions2mm 10 lesionsgt2 2 (3mm) lesionsCoalescent 1 (4mm)
lesions R
Left Lung Right Lung
11
112
869
29
34
N
M
L
NO
Q
Qx Group05mm 1 lesion
05mm 5 lesions1mm 4 lesions2mm 1 lesion
05mm 5 lesions1mm 5 lesions2mm 1 lesion
05mm 1 lesion
1mm 1 lesion
05mm 8 lesions1mm 38 lesions2mm 2 lesionsgt2 3 (3mm) 1 (5mm)
1(6mm) lesionsCoalescent 1 (5mm) lesion
M
P
Left Lung Right Lung
1
54
1
11
10
1
R
L
NOR
Q
P
RUTI Group05mm 1 lesion
05mm 3 lesions1mm 3 lesions
05mm 1 lesion1mm 2 lesions
gt2mm 1 (3mm) lesion
05mm 6 lesions1mm 20 lesions2mm 8 lesionsgt2 2 (3mm) 1 (4mm)
lesions
M
Left Lung Right Lung
35 3
6
11
05mm 1mm 2mm gt2 Coalescent
Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
INH x 4weeksbull reduced granulomabull Reduced dissemination of infectionbull Retarded evolution of granulomabullDid not induce TB specific immunity
INH x 4wks + RUTI x 2bull reduced granulomabullReduced dissemination of infectionbull Promoted evolution of granulomabull Induced TB specific immunity
(Gill O PLoS ONE 5(4) e10030 doi101371journalpone0010030)
Conclusion
bull HIV associated TB accounts for the vast majority of TB in sub-Saharan Africa
bull Need new safe short effective regimens for HIV associated TB including MXDR TB
bull Use of adjunctive immunotherapy should be evaluated
bull Need new safe short effective regimens for treating LTBI particularly for DR TB
bull Therapeutic TB vaccines required
Acknowledgements
bull Helen McIlleronbull Ann Ginsburg
- Issues in TB Drug DevelopmentTBHIV
- Presentation outline
- SA has one of the worst TB epidemics in the world
- Integrated TB and HIV treatment saves lives
- Projected use of PI-based ART
- Slide Number 6
- Effect of IPT and ART on TB incidence and mortality
- Effect of IPT and ART on TB incidence and mortality
- Reduction in TB incidence with 36 vs 6 months IPT
- Reduction in TB incidence with 36 vs 6 months IPT
- New drugs amp regimens required for HIV associated TB
- Rifapentine ndash food interactions
- Potential interactions bw fluroquinolones and antiretrovirals
- PXR regulates drug-metabolizing enzymes
- Rifampicin is a potent activator of PXR
- Drug-Drug Interactions
- Combined toxicities
- Role of adjunctive immunotherapy
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
- Supplementing effector cytokines to assist with antimicrobial activity
- Preventing HIV associated TB
- Isoniazid preventive therapy
- Slide Number 25
- LTBI with MDRXDR TB
- Slide Number 27
- Treatment of LTBI
- Slide Number 29
- Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
- Conclusion
- Acknowledgements
-
Rifampicin is a potent activator of PXR
CYP2B6
CYP2C9CYP2C8
CYP2B9
CYP3A4
UGTs
GSTs
SULTs
PXR-RXR
APBL
MRP2
OATP2
MDR1
Activating ligands trigger altered expression of multiple of enzymes and transporters with
compound effects on substrate concentrations
DRUG
RIF
OATP1B1
CYP3A7
J Pharmacol Exp Ther 2003 304 223-28
Drug InteractionsDiarylquinolines(TMC207)
bullCYP 3A4 SubstratebullNo PK interactions with HZbullPK studies with EFV NVP LPVr awaited
Ethylene Diamines (SQ-109)
CYP 2D6 CYP 2C19 substrate
Nitroimidazoles (PA-824 OPC-67683)
Not metabolized by or interfere with CYP enzymes
oxazolidinones (PNU-100480 Linezolid )
Mono Aminine Oxidase InhibitorsNot metabolized by or interfere with drug metabolizing enzymes
Drug-Drug Interactions
(Source H McIlleron)
Combined toxicities
Example of Linezolidbull CNS toxicity EFVbull Peripheral neuropathy DDI D4Tbull Lactic acidosis D4Tbull Myelosuppression ZDV
(Source H McIlleron)
Role of adjunctive immunotherapy
bull Shortening the duration of TB treatment bull Improve treatment success of M(X)DR TBbull Reduce clinical complicationsbull Reduce rate of recurrent TB
Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
GMP manufacturing capacity existsIvIgHE2000 M vaccaeanti-IL-4 RUTI
GMP capacity to be establishedhsp65 DNA vaccine
OtherDzherelo
Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
GMP manufacturing capacity existsIvIgHE2000 M vaccaeanti-IL-4 RUTI
GMP capacity to be establishedhsp65 DNA vaccine
OtherDzherelo
bull Thalidomide analogsndash Inhibit TNFα which is essential for granuloma
formationbull Entanercept (soluble TNF receptor)bull High dose prednisone
Concernsbull Requires concomitant bactericidal therapybull Agents inhibit protective immunity thereby
facilitating growth of organismsbull immunosuppression may result in OIs
Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
Supplementing effector cytokines to assist with antimicrobial activityRh-IFN-γ amp αRh-IL-2Rh-GM-CSFIL-12
Preventing HIV associated TB
Latent TB infection
TB disease
Treatment of latent TB infection
bull Isoniazid preventive therapy
Restore boost protective immunitybull ARTbull PrePost exposure TB vaccines
Isoniazid preventive therapy
bull Good safety profilebull Effective cheap amp readily availablebull Public health benefitBUTbull Requires a long treatment periodbull TB rates remain high in pts with advanced
HIV diseasebull Limited durabilitybull Adherence problematicbull Concern about promoting resistance
bull Efficacy compared to INH
TB incidence rate ratio (RR)minus INH (13) RR = 067minus INH + RIF (2) RR = 041minus RIF + PZA (4) RR = 054minus INH RIF + PZA (1) RR = 048
bull Increased side effects resulting in discontinuation
Multi-drug TB preventive therapyregimens
LTBI with MDRXDR TB
bull MDR TB increased globallybull Close contacts of MDRXDR TB patients are
at increased risk of becoming infectedbull PLHIV infected with MDRXDR TB are at
high risk of progressing to diseasebull Almost no data and inconsistent
international guidelines for treating contacts of MDR TB patients
HIV associated MDR amp XDR TB in SA
(N Gandhi Am J Resp Crit Care Med 2009)
Treatment of LTBIbull Effective tolerable ultra short course
treatment for DS LTBI requiredndash Mouse model of LTBI
(Eric Nuermberger) bull JgtRgtRHbull J=P=HPbull JPgtPZ
bull Effective treatment for LTBI with MDRXDR TB urgently neededndash need to evaluate regimens in mouse model
0003
006009
0003
006009
01
10
100
1000
10000
New TB cases
million in 2050
Treatment ratelatentyr
Vaccinations uninfected yr
ELIMINATING TB BY 2050BY PREVENTING INFECTION AND TREATING LATENT
INFECTIONEliminating TB by 2050Requires both PT and vaccines
M
8
L
O
Q
P
Control Group05mm 3 lesions1mm 25 lesions2mm 6 lesions
05mm 18 lesions1mm 8 lesions2mm 3 lesions
05mm 53 lesions1mm 13 lesions2mm 3 lesions
05mm 4 lesions1mm 1 lesions2mm 3 lesions
05mm 4 lesions1mm 3 lesions2mm 1 lesion
05mm 7 lesions1mm 4 lesions
05mm 24 lesions1mm 75 lesions2mm 10 lesionsgt2 2 (3mm) lesionsCoalescent 1 (4mm)
lesions R
Left Lung Right Lung
11
112
869
29
34
N
M
L
NO
Q
Qx Group05mm 1 lesion
05mm 5 lesions1mm 4 lesions2mm 1 lesion
05mm 5 lesions1mm 5 lesions2mm 1 lesion
05mm 1 lesion
1mm 1 lesion
05mm 8 lesions1mm 38 lesions2mm 2 lesionsgt2 3 (3mm) 1 (5mm)
1(6mm) lesionsCoalescent 1 (5mm) lesion
M
P
Left Lung Right Lung
1
54
1
11
10
1
R
L
NOR
Q
P
RUTI Group05mm 1 lesion
05mm 3 lesions1mm 3 lesions
05mm 1 lesion1mm 2 lesions
gt2mm 1 (3mm) lesion
05mm 6 lesions1mm 20 lesions2mm 8 lesionsgt2 2 (3mm) 1 (4mm)
lesions
M
Left Lung Right Lung
35 3
6
11
05mm 1mm 2mm gt2 Coalescent
Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
INH x 4weeksbull reduced granulomabull Reduced dissemination of infectionbull Retarded evolution of granulomabullDid not induce TB specific immunity
INH x 4wks + RUTI x 2bull reduced granulomabullReduced dissemination of infectionbull Promoted evolution of granulomabull Induced TB specific immunity
(Gill O PLoS ONE 5(4) e10030 doi101371journalpone0010030)
Conclusion
bull HIV associated TB accounts for the vast majority of TB in sub-Saharan Africa
bull Need new safe short effective regimens for HIV associated TB including MXDR TB
bull Use of adjunctive immunotherapy should be evaluated
bull Need new safe short effective regimens for treating LTBI particularly for DR TB
bull Therapeutic TB vaccines required
Acknowledgements
bull Helen McIlleronbull Ann Ginsburg
- Issues in TB Drug DevelopmentTBHIV
- Presentation outline
- SA has one of the worst TB epidemics in the world
- Integrated TB and HIV treatment saves lives
- Projected use of PI-based ART
- Slide Number 6
- Effect of IPT and ART on TB incidence and mortality
- Effect of IPT and ART on TB incidence and mortality
- Reduction in TB incidence with 36 vs 6 months IPT
- Reduction in TB incidence with 36 vs 6 months IPT
- New drugs amp regimens required for HIV associated TB
- Rifapentine ndash food interactions
- Potential interactions bw fluroquinolones and antiretrovirals
- PXR regulates drug-metabolizing enzymes
- Rifampicin is a potent activator of PXR
- Drug-Drug Interactions
- Combined toxicities
- Role of adjunctive immunotherapy
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
- Supplementing effector cytokines to assist with antimicrobial activity
- Preventing HIV associated TB
- Isoniazid preventive therapy
- Slide Number 25
- LTBI with MDRXDR TB
- Slide Number 27
- Treatment of LTBI
- Slide Number 29
- Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
- Conclusion
- Acknowledgements
-
Drug InteractionsDiarylquinolines(TMC207)
bullCYP 3A4 SubstratebullNo PK interactions with HZbullPK studies with EFV NVP LPVr awaited
Ethylene Diamines (SQ-109)
CYP 2D6 CYP 2C19 substrate
Nitroimidazoles (PA-824 OPC-67683)
Not metabolized by or interfere with CYP enzymes
oxazolidinones (PNU-100480 Linezolid )
Mono Aminine Oxidase InhibitorsNot metabolized by or interfere with drug metabolizing enzymes
Drug-Drug Interactions
(Source H McIlleron)
Combined toxicities
Example of Linezolidbull CNS toxicity EFVbull Peripheral neuropathy DDI D4Tbull Lactic acidosis D4Tbull Myelosuppression ZDV
(Source H McIlleron)
Role of adjunctive immunotherapy
bull Shortening the duration of TB treatment bull Improve treatment success of M(X)DR TBbull Reduce clinical complicationsbull Reduce rate of recurrent TB
Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
GMP manufacturing capacity existsIvIgHE2000 M vaccaeanti-IL-4 RUTI
GMP capacity to be establishedhsp65 DNA vaccine
OtherDzherelo
Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
GMP manufacturing capacity existsIvIgHE2000 M vaccaeanti-IL-4 RUTI
GMP capacity to be establishedhsp65 DNA vaccine
OtherDzherelo
bull Thalidomide analogsndash Inhibit TNFα which is essential for granuloma
formationbull Entanercept (soluble TNF receptor)bull High dose prednisone
Concernsbull Requires concomitant bactericidal therapybull Agents inhibit protective immunity thereby
facilitating growth of organismsbull immunosuppression may result in OIs
Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
Supplementing effector cytokines to assist with antimicrobial activityRh-IFN-γ amp αRh-IL-2Rh-GM-CSFIL-12
Preventing HIV associated TB
Latent TB infection
TB disease
Treatment of latent TB infection
bull Isoniazid preventive therapy
Restore boost protective immunitybull ARTbull PrePost exposure TB vaccines
Isoniazid preventive therapy
bull Good safety profilebull Effective cheap amp readily availablebull Public health benefitBUTbull Requires a long treatment periodbull TB rates remain high in pts with advanced
HIV diseasebull Limited durabilitybull Adherence problematicbull Concern about promoting resistance
bull Efficacy compared to INH
TB incidence rate ratio (RR)minus INH (13) RR = 067minus INH + RIF (2) RR = 041minus RIF + PZA (4) RR = 054minus INH RIF + PZA (1) RR = 048
bull Increased side effects resulting in discontinuation
Multi-drug TB preventive therapyregimens
LTBI with MDRXDR TB
bull MDR TB increased globallybull Close contacts of MDRXDR TB patients are
at increased risk of becoming infectedbull PLHIV infected with MDRXDR TB are at
high risk of progressing to diseasebull Almost no data and inconsistent
international guidelines for treating contacts of MDR TB patients
HIV associated MDR amp XDR TB in SA
(N Gandhi Am J Resp Crit Care Med 2009)
Treatment of LTBIbull Effective tolerable ultra short course
treatment for DS LTBI requiredndash Mouse model of LTBI
(Eric Nuermberger) bull JgtRgtRHbull J=P=HPbull JPgtPZ
bull Effective treatment for LTBI with MDRXDR TB urgently neededndash need to evaluate regimens in mouse model
0003
006009
0003
006009
01
10
100
1000
10000
New TB cases
million in 2050
Treatment ratelatentyr
Vaccinations uninfected yr
ELIMINATING TB BY 2050BY PREVENTING INFECTION AND TREATING LATENT
INFECTIONEliminating TB by 2050Requires both PT and vaccines
M
8
L
O
Q
P
Control Group05mm 3 lesions1mm 25 lesions2mm 6 lesions
05mm 18 lesions1mm 8 lesions2mm 3 lesions
05mm 53 lesions1mm 13 lesions2mm 3 lesions
05mm 4 lesions1mm 1 lesions2mm 3 lesions
05mm 4 lesions1mm 3 lesions2mm 1 lesion
05mm 7 lesions1mm 4 lesions
05mm 24 lesions1mm 75 lesions2mm 10 lesionsgt2 2 (3mm) lesionsCoalescent 1 (4mm)
lesions R
Left Lung Right Lung
11
112
869
29
34
N
M
L
NO
Q
Qx Group05mm 1 lesion
05mm 5 lesions1mm 4 lesions2mm 1 lesion
05mm 5 lesions1mm 5 lesions2mm 1 lesion
05mm 1 lesion
1mm 1 lesion
05mm 8 lesions1mm 38 lesions2mm 2 lesionsgt2 3 (3mm) 1 (5mm)
1(6mm) lesionsCoalescent 1 (5mm) lesion
M
P
Left Lung Right Lung
1
54
1
11
10
1
R
L
NOR
Q
P
RUTI Group05mm 1 lesion
05mm 3 lesions1mm 3 lesions
05mm 1 lesion1mm 2 lesions
gt2mm 1 (3mm) lesion
05mm 6 lesions1mm 20 lesions2mm 8 lesionsgt2 2 (3mm) 1 (4mm)
lesions
M
Left Lung Right Lung
35 3
6
11
05mm 1mm 2mm gt2 Coalescent
Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
INH x 4weeksbull reduced granulomabull Reduced dissemination of infectionbull Retarded evolution of granulomabullDid not induce TB specific immunity
INH x 4wks + RUTI x 2bull reduced granulomabullReduced dissemination of infectionbull Promoted evolution of granulomabull Induced TB specific immunity
(Gill O PLoS ONE 5(4) e10030 doi101371journalpone0010030)
Conclusion
bull HIV associated TB accounts for the vast majority of TB in sub-Saharan Africa
bull Need new safe short effective regimens for HIV associated TB including MXDR TB
bull Use of adjunctive immunotherapy should be evaluated
bull Need new safe short effective regimens for treating LTBI particularly for DR TB
bull Therapeutic TB vaccines required
Acknowledgements
bull Helen McIlleronbull Ann Ginsburg
- Issues in TB Drug DevelopmentTBHIV
- Presentation outline
- SA has one of the worst TB epidemics in the world
- Integrated TB and HIV treatment saves lives
- Projected use of PI-based ART
- Slide Number 6
- Effect of IPT and ART on TB incidence and mortality
- Effect of IPT and ART on TB incidence and mortality
- Reduction in TB incidence with 36 vs 6 months IPT
- Reduction in TB incidence with 36 vs 6 months IPT
- New drugs amp regimens required for HIV associated TB
- Rifapentine ndash food interactions
- Potential interactions bw fluroquinolones and antiretrovirals
- PXR regulates drug-metabolizing enzymes
- Rifampicin is a potent activator of PXR
- Drug-Drug Interactions
- Combined toxicities
- Role of adjunctive immunotherapy
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
- Supplementing effector cytokines to assist with antimicrobial activity
- Preventing HIV associated TB
- Isoniazid preventive therapy
- Slide Number 25
- LTBI with MDRXDR TB
- Slide Number 27
- Treatment of LTBI
- Slide Number 29
- Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
- Conclusion
- Acknowledgements
-
Combined toxicities
Example of Linezolidbull CNS toxicity EFVbull Peripheral neuropathy DDI D4Tbull Lactic acidosis D4Tbull Myelosuppression ZDV
(Source H McIlleron)
Role of adjunctive immunotherapy
bull Shortening the duration of TB treatment bull Improve treatment success of M(X)DR TBbull Reduce clinical complicationsbull Reduce rate of recurrent TB
Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
GMP manufacturing capacity existsIvIgHE2000 M vaccaeanti-IL-4 RUTI
GMP capacity to be establishedhsp65 DNA vaccine
OtherDzherelo
Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
GMP manufacturing capacity existsIvIgHE2000 M vaccaeanti-IL-4 RUTI
GMP capacity to be establishedhsp65 DNA vaccine
OtherDzherelo
bull Thalidomide analogsndash Inhibit TNFα which is essential for granuloma
formationbull Entanercept (soluble TNF receptor)bull High dose prednisone
Concernsbull Requires concomitant bactericidal therapybull Agents inhibit protective immunity thereby
facilitating growth of organismsbull immunosuppression may result in OIs
Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
Supplementing effector cytokines to assist with antimicrobial activityRh-IFN-γ amp αRh-IL-2Rh-GM-CSFIL-12
Preventing HIV associated TB
Latent TB infection
TB disease
Treatment of latent TB infection
bull Isoniazid preventive therapy
Restore boost protective immunitybull ARTbull PrePost exposure TB vaccines
Isoniazid preventive therapy
bull Good safety profilebull Effective cheap amp readily availablebull Public health benefitBUTbull Requires a long treatment periodbull TB rates remain high in pts with advanced
HIV diseasebull Limited durabilitybull Adherence problematicbull Concern about promoting resistance
bull Efficacy compared to INH
TB incidence rate ratio (RR)minus INH (13) RR = 067minus INH + RIF (2) RR = 041minus RIF + PZA (4) RR = 054minus INH RIF + PZA (1) RR = 048
bull Increased side effects resulting in discontinuation
Multi-drug TB preventive therapyregimens
LTBI with MDRXDR TB
bull MDR TB increased globallybull Close contacts of MDRXDR TB patients are
at increased risk of becoming infectedbull PLHIV infected with MDRXDR TB are at
high risk of progressing to diseasebull Almost no data and inconsistent
international guidelines for treating contacts of MDR TB patients
HIV associated MDR amp XDR TB in SA
(N Gandhi Am J Resp Crit Care Med 2009)
Treatment of LTBIbull Effective tolerable ultra short course
treatment for DS LTBI requiredndash Mouse model of LTBI
(Eric Nuermberger) bull JgtRgtRHbull J=P=HPbull JPgtPZ
bull Effective treatment for LTBI with MDRXDR TB urgently neededndash need to evaluate regimens in mouse model
0003
006009
0003
006009
01
10
100
1000
10000
New TB cases
million in 2050
Treatment ratelatentyr
Vaccinations uninfected yr
ELIMINATING TB BY 2050BY PREVENTING INFECTION AND TREATING LATENT
INFECTIONEliminating TB by 2050Requires both PT and vaccines
M
8
L
O
Q
P
Control Group05mm 3 lesions1mm 25 lesions2mm 6 lesions
05mm 18 lesions1mm 8 lesions2mm 3 lesions
05mm 53 lesions1mm 13 lesions2mm 3 lesions
05mm 4 lesions1mm 1 lesions2mm 3 lesions
05mm 4 lesions1mm 3 lesions2mm 1 lesion
05mm 7 lesions1mm 4 lesions
05mm 24 lesions1mm 75 lesions2mm 10 lesionsgt2 2 (3mm) lesionsCoalescent 1 (4mm)
lesions R
Left Lung Right Lung
11
112
869
29
34
N
M
L
NO
Q
Qx Group05mm 1 lesion
05mm 5 lesions1mm 4 lesions2mm 1 lesion
05mm 5 lesions1mm 5 lesions2mm 1 lesion
05mm 1 lesion
1mm 1 lesion
05mm 8 lesions1mm 38 lesions2mm 2 lesionsgt2 3 (3mm) 1 (5mm)
1(6mm) lesionsCoalescent 1 (5mm) lesion
M
P
Left Lung Right Lung
1
54
1
11
10
1
R
L
NOR
Q
P
RUTI Group05mm 1 lesion
05mm 3 lesions1mm 3 lesions
05mm 1 lesion1mm 2 lesions
gt2mm 1 (3mm) lesion
05mm 6 lesions1mm 20 lesions2mm 8 lesionsgt2 2 (3mm) 1 (4mm)
lesions
M
Left Lung Right Lung
35 3
6
11
05mm 1mm 2mm gt2 Coalescent
Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
INH x 4weeksbull reduced granulomabull Reduced dissemination of infectionbull Retarded evolution of granulomabullDid not induce TB specific immunity
INH x 4wks + RUTI x 2bull reduced granulomabullReduced dissemination of infectionbull Promoted evolution of granulomabull Induced TB specific immunity
(Gill O PLoS ONE 5(4) e10030 doi101371journalpone0010030)
Conclusion
bull HIV associated TB accounts for the vast majority of TB in sub-Saharan Africa
bull Need new safe short effective regimens for HIV associated TB including MXDR TB
bull Use of adjunctive immunotherapy should be evaluated
bull Need new safe short effective regimens for treating LTBI particularly for DR TB
bull Therapeutic TB vaccines required
Acknowledgements
bull Helen McIlleronbull Ann Ginsburg
- Issues in TB Drug DevelopmentTBHIV
- Presentation outline
- SA has one of the worst TB epidemics in the world
- Integrated TB and HIV treatment saves lives
- Projected use of PI-based ART
- Slide Number 6
- Effect of IPT and ART on TB incidence and mortality
- Effect of IPT and ART on TB incidence and mortality
- Reduction in TB incidence with 36 vs 6 months IPT
- Reduction in TB incidence with 36 vs 6 months IPT
- New drugs amp regimens required for HIV associated TB
- Rifapentine ndash food interactions
- Potential interactions bw fluroquinolones and antiretrovirals
- PXR regulates drug-metabolizing enzymes
- Rifampicin is a potent activator of PXR
- Drug-Drug Interactions
- Combined toxicities
- Role of adjunctive immunotherapy
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
- Supplementing effector cytokines to assist with antimicrobial activity
- Preventing HIV associated TB
- Isoniazid preventive therapy
- Slide Number 25
- LTBI with MDRXDR TB
- Slide Number 27
- Treatment of LTBI
- Slide Number 29
- Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
- Conclusion
- Acknowledgements
-
Role of adjunctive immunotherapy
bull Shortening the duration of TB treatment bull Improve treatment success of M(X)DR TBbull Reduce clinical complicationsbull Reduce rate of recurrent TB
Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
GMP manufacturing capacity existsIvIgHE2000 M vaccaeanti-IL-4 RUTI
GMP capacity to be establishedhsp65 DNA vaccine
OtherDzherelo
Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
GMP manufacturing capacity existsIvIgHE2000 M vaccaeanti-IL-4 RUTI
GMP capacity to be establishedhsp65 DNA vaccine
OtherDzherelo
bull Thalidomide analogsndash Inhibit TNFα which is essential for granuloma
formationbull Entanercept (soluble TNF receptor)bull High dose prednisone
Concernsbull Requires concomitant bactericidal therapybull Agents inhibit protective immunity thereby
facilitating growth of organismsbull immunosuppression may result in OIs
Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
Supplementing effector cytokines to assist with antimicrobial activityRh-IFN-γ amp αRh-IL-2Rh-GM-CSFIL-12
Preventing HIV associated TB
Latent TB infection
TB disease
Treatment of latent TB infection
bull Isoniazid preventive therapy
Restore boost protective immunitybull ARTbull PrePost exposure TB vaccines
Isoniazid preventive therapy
bull Good safety profilebull Effective cheap amp readily availablebull Public health benefitBUTbull Requires a long treatment periodbull TB rates remain high in pts with advanced
HIV diseasebull Limited durabilitybull Adherence problematicbull Concern about promoting resistance
bull Efficacy compared to INH
TB incidence rate ratio (RR)minus INH (13) RR = 067minus INH + RIF (2) RR = 041minus RIF + PZA (4) RR = 054minus INH RIF + PZA (1) RR = 048
bull Increased side effects resulting in discontinuation
Multi-drug TB preventive therapyregimens
LTBI with MDRXDR TB
bull MDR TB increased globallybull Close contacts of MDRXDR TB patients are
at increased risk of becoming infectedbull PLHIV infected with MDRXDR TB are at
high risk of progressing to diseasebull Almost no data and inconsistent
international guidelines for treating contacts of MDR TB patients
HIV associated MDR amp XDR TB in SA
(N Gandhi Am J Resp Crit Care Med 2009)
Treatment of LTBIbull Effective tolerable ultra short course
treatment for DS LTBI requiredndash Mouse model of LTBI
(Eric Nuermberger) bull JgtRgtRHbull J=P=HPbull JPgtPZ
bull Effective treatment for LTBI with MDRXDR TB urgently neededndash need to evaluate regimens in mouse model
0003
006009
0003
006009
01
10
100
1000
10000
New TB cases
million in 2050
Treatment ratelatentyr
Vaccinations uninfected yr
ELIMINATING TB BY 2050BY PREVENTING INFECTION AND TREATING LATENT
INFECTIONEliminating TB by 2050Requires both PT and vaccines
M
8
L
O
Q
P
Control Group05mm 3 lesions1mm 25 lesions2mm 6 lesions
05mm 18 lesions1mm 8 lesions2mm 3 lesions
05mm 53 lesions1mm 13 lesions2mm 3 lesions
05mm 4 lesions1mm 1 lesions2mm 3 lesions
05mm 4 lesions1mm 3 lesions2mm 1 lesion
05mm 7 lesions1mm 4 lesions
05mm 24 lesions1mm 75 lesions2mm 10 lesionsgt2 2 (3mm) lesionsCoalescent 1 (4mm)
lesions R
Left Lung Right Lung
11
112
869
29
34
N
M
L
NO
Q
Qx Group05mm 1 lesion
05mm 5 lesions1mm 4 lesions2mm 1 lesion
05mm 5 lesions1mm 5 lesions2mm 1 lesion
05mm 1 lesion
1mm 1 lesion
05mm 8 lesions1mm 38 lesions2mm 2 lesionsgt2 3 (3mm) 1 (5mm)
1(6mm) lesionsCoalescent 1 (5mm) lesion
M
P
Left Lung Right Lung
1
54
1
11
10
1
R
L
NOR
Q
P
RUTI Group05mm 1 lesion
05mm 3 lesions1mm 3 lesions
05mm 1 lesion1mm 2 lesions
gt2mm 1 (3mm) lesion
05mm 6 lesions1mm 20 lesions2mm 8 lesionsgt2 2 (3mm) 1 (4mm)
lesions
M
Left Lung Right Lung
35 3
6
11
05mm 1mm 2mm gt2 Coalescent
Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
INH x 4weeksbull reduced granulomabull Reduced dissemination of infectionbull Retarded evolution of granulomabullDid not induce TB specific immunity
INH x 4wks + RUTI x 2bull reduced granulomabullReduced dissemination of infectionbull Promoted evolution of granulomabull Induced TB specific immunity
(Gill O PLoS ONE 5(4) e10030 doi101371journalpone0010030)
Conclusion
bull HIV associated TB accounts for the vast majority of TB in sub-Saharan Africa
bull Need new safe short effective regimens for HIV associated TB including MXDR TB
bull Use of adjunctive immunotherapy should be evaluated
bull Need new safe short effective regimens for treating LTBI particularly for DR TB
bull Therapeutic TB vaccines required
Acknowledgements
bull Helen McIlleronbull Ann Ginsburg
- Issues in TB Drug DevelopmentTBHIV
- Presentation outline
- SA has one of the worst TB epidemics in the world
- Integrated TB and HIV treatment saves lives
- Projected use of PI-based ART
- Slide Number 6
- Effect of IPT and ART on TB incidence and mortality
- Effect of IPT and ART on TB incidence and mortality
- Reduction in TB incidence with 36 vs 6 months IPT
- Reduction in TB incidence with 36 vs 6 months IPT
- New drugs amp regimens required for HIV associated TB
- Rifapentine ndash food interactions
- Potential interactions bw fluroquinolones and antiretrovirals
- PXR regulates drug-metabolizing enzymes
- Rifampicin is a potent activator of PXR
- Drug-Drug Interactions
- Combined toxicities
- Role of adjunctive immunotherapy
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
- Supplementing effector cytokines to assist with antimicrobial activity
- Preventing HIV associated TB
- Isoniazid preventive therapy
- Slide Number 25
- LTBI with MDRXDR TB
- Slide Number 27
- Treatment of LTBI
- Slide Number 29
- Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
- Conclusion
- Acknowledgements
-
Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
GMP manufacturing capacity existsIvIgHE2000 M vaccaeanti-IL-4 RUTI
GMP capacity to be establishedhsp65 DNA vaccine
OtherDzherelo
Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
GMP manufacturing capacity existsIvIgHE2000 M vaccaeanti-IL-4 RUTI
GMP capacity to be establishedhsp65 DNA vaccine
OtherDzherelo
bull Thalidomide analogsndash Inhibit TNFα which is essential for granuloma
formationbull Entanercept (soluble TNF receptor)bull High dose prednisone
Concernsbull Requires concomitant bactericidal therapybull Agents inhibit protective immunity thereby
facilitating growth of organismsbull immunosuppression may result in OIs
Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
Supplementing effector cytokines to assist with antimicrobial activityRh-IFN-γ amp αRh-IL-2Rh-GM-CSFIL-12
Preventing HIV associated TB
Latent TB infection
TB disease
Treatment of latent TB infection
bull Isoniazid preventive therapy
Restore boost protective immunitybull ARTbull PrePost exposure TB vaccines
Isoniazid preventive therapy
bull Good safety profilebull Effective cheap amp readily availablebull Public health benefitBUTbull Requires a long treatment periodbull TB rates remain high in pts with advanced
HIV diseasebull Limited durabilitybull Adherence problematicbull Concern about promoting resistance
bull Efficacy compared to INH
TB incidence rate ratio (RR)minus INH (13) RR = 067minus INH + RIF (2) RR = 041minus RIF + PZA (4) RR = 054minus INH RIF + PZA (1) RR = 048
bull Increased side effects resulting in discontinuation
Multi-drug TB preventive therapyregimens
LTBI with MDRXDR TB
bull MDR TB increased globallybull Close contacts of MDRXDR TB patients are
at increased risk of becoming infectedbull PLHIV infected with MDRXDR TB are at
high risk of progressing to diseasebull Almost no data and inconsistent
international guidelines for treating contacts of MDR TB patients
HIV associated MDR amp XDR TB in SA
(N Gandhi Am J Resp Crit Care Med 2009)
Treatment of LTBIbull Effective tolerable ultra short course
treatment for DS LTBI requiredndash Mouse model of LTBI
(Eric Nuermberger) bull JgtRgtRHbull J=P=HPbull JPgtPZ
bull Effective treatment for LTBI with MDRXDR TB urgently neededndash need to evaluate regimens in mouse model
0003
006009
0003
006009
01
10
100
1000
10000
New TB cases
million in 2050
Treatment ratelatentyr
Vaccinations uninfected yr
ELIMINATING TB BY 2050BY PREVENTING INFECTION AND TREATING LATENT
INFECTIONEliminating TB by 2050Requires both PT and vaccines
M
8
L
O
Q
P
Control Group05mm 3 lesions1mm 25 lesions2mm 6 lesions
05mm 18 lesions1mm 8 lesions2mm 3 lesions
05mm 53 lesions1mm 13 lesions2mm 3 lesions
05mm 4 lesions1mm 1 lesions2mm 3 lesions
05mm 4 lesions1mm 3 lesions2mm 1 lesion
05mm 7 lesions1mm 4 lesions
05mm 24 lesions1mm 75 lesions2mm 10 lesionsgt2 2 (3mm) lesionsCoalescent 1 (4mm)
lesions R
Left Lung Right Lung
11
112
869
29
34
N
M
L
NO
Q
Qx Group05mm 1 lesion
05mm 5 lesions1mm 4 lesions2mm 1 lesion
05mm 5 lesions1mm 5 lesions2mm 1 lesion
05mm 1 lesion
1mm 1 lesion
05mm 8 lesions1mm 38 lesions2mm 2 lesionsgt2 3 (3mm) 1 (5mm)
1(6mm) lesionsCoalescent 1 (5mm) lesion
M
P
Left Lung Right Lung
1
54
1
11
10
1
R
L
NOR
Q
P
RUTI Group05mm 1 lesion
05mm 3 lesions1mm 3 lesions
05mm 1 lesion1mm 2 lesions
gt2mm 1 (3mm) lesion
05mm 6 lesions1mm 20 lesions2mm 8 lesionsgt2 2 (3mm) 1 (4mm)
lesions
M
Left Lung Right Lung
35 3
6
11
05mm 1mm 2mm gt2 Coalescent
Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
INH x 4weeksbull reduced granulomabull Reduced dissemination of infectionbull Retarded evolution of granulomabullDid not induce TB specific immunity
INH x 4wks + RUTI x 2bull reduced granulomabullReduced dissemination of infectionbull Promoted evolution of granulomabull Induced TB specific immunity
(Gill O PLoS ONE 5(4) e10030 doi101371journalpone0010030)
Conclusion
bull HIV associated TB accounts for the vast majority of TB in sub-Saharan Africa
bull Need new safe short effective regimens for HIV associated TB including MXDR TB
bull Use of adjunctive immunotherapy should be evaluated
bull Need new safe short effective regimens for treating LTBI particularly for DR TB
bull Therapeutic TB vaccines required
Acknowledgements
bull Helen McIlleronbull Ann Ginsburg
- Issues in TB Drug DevelopmentTBHIV
- Presentation outline
- SA has one of the worst TB epidemics in the world
- Integrated TB and HIV treatment saves lives
- Projected use of PI-based ART
- Slide Number 6
- Effect of IPT and ART on TB incidence and mortality
- Effect of IPT and ART on TB incidence and mortality
- Reduction in TB incidence with 36 vs 6 months IPT
- Reduction in TB incidence with 36 vs 6 months IPT
- New drugs amp regimens required for HIV associated TB
- Rifapentine ndash food interactions
- Potential interactions bw fluroquinolones and antiretrovirals
- PXR regulates drug-metabolizing enzymes
- Rifampicin is a potent activator of PXR
- Drug-Drug Interactions
- Combined toxicities
- Role of adjunctive immunotherapy
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
- Supplementing effector cytokines to assist with antimicrobial activity
- Preventing HIV associated TB
- Isoniazid preventive therapy
- Slide Number 25
- LTBI with MDRXDR TB
- Slide Number 27
- Treatment of LTBI
- Slide Number 29
- Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
- Conclusion
- Acknowledgements
-
Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
GMP manufacturing capacity existsIvIgHE2000 M vaccaeanti-IL-4 RUTI
GMP capacity to be establishedhsp65 DNA vaccine
OtherDzherelo
bull Thalidomide analogsndash Inhibit TNFα which is essential for granuloma
formationbull Entanercept (soluble TNF receptor)bull High dose prednisone
Concernsbull Requires concomitant bactericidal therapybull Agents inhibit protective immunity thereby
facilitating growth of organismsbull immunosuppression may result in OIs
Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
Supplementing effector cytokines to assist with antimicrobial activityRh-IFN-γ amp αRh-IL-2Rh-GM-CSFIL-12
Preventing HIV associated TB
Latent TB infection
TB disease
Treatment of latent TB infection
bull Isoniazid preventive therapy
Restore boost protective immunitybull ARTbull PrePost exposure TB vaccines
Isoniazid preventive therapy
bull Good safety profilebull Effective cheap amp readily availablebull Public health benefitBUTbull Requires a long treatment periodbull TB rates remain high in pts with advanced
HIV diseasebull Limited durabilitybull Adherence problematicbull Concern about promoting resistance
bull Efficacy compared to INH
TB incidence rate ratio (RR)minus INH (13) RR = 067minus INH + RIF (2) RR = 041minus RIF + PZA (4) RR = 054minus INH RIF + PZA (1) RR = 048
bull Increased side effects resulting in discontinuation
Multi-drug TB preventive therapyregimens
LTBI with MDRXDR TB
bull MDR TB increased globallybull Close contacts of MDRXDR TB patients are
at increased risk of becoming infectedbull PLHIV infected with MDRXDR TB are at
high risk of progressing to diseasebull Almost no data and inconsistent
international guidelines for treating contacts of MDR TB patients
HIV associated MDR amp XDR TB in SA
(N Gandhi Am J Resp Crit Care Med 2009)
Treatment of LTBIbull Effective tolerable ultra short course
treatment for DS LTBI requiredndash Mouse model of LTBI
(Eric Nuermberger) bull JgtRgtRHbull J=P=HPbull JPgtPZ
bull Effective treatment for LTBI with MDRXDR TB urgently neededndash need to evaluate regimens in mouse model
0003
006009
0003
006009
01
10
100
1000
10000
New TB cases
million in 2050
Treatment ratelatentyr
Vaccinations uninfected yr
ELIMINATING TB BY 2050BY PREVENTING INFECTION AND TREATING LATENT
INFECTIONEliminating TB by 2050Requires both PT and vaccines
M
8
L
O
Q
P
Control Group05mm 3 lesions1mm 25 lesions2mm 6 lesions
05mm 18 lesions1mm 8 lesions2mm 3 lesions
05mm 53 lesions1mm 13 lesions2mm 3 lesions
05mm 4 lesions1mm 1 lesions2mm 3 lesions
05mm 4 lesions1mm 3 lesions2mm 1 lesion
05mm 7 lesions1mm 4 lesions
05mm 24 lesions1mm 75 lesions2mm 10 lesionsgt2 2 (3mm) lesionsCoalescent 1 (4mm)
lesions R
Left Lung Right Lung
11
112
869
29
34
N
M
L
NO
Q
Qx Group05mm 1 lesion
05mm 5 lesions1mm 4 lesions2mm 1 lesion
05mm 5 lesions1mm 5 lesions2mm 1 lesion
05mm 1 lesion
1mm 1 lesion
05mm 8 lesions1mm 38 lesions2mm 2 lesionsgt2 3 (3mm) 1 (5mm)
1(6mm) lesionsCoalescent 1 (5mm) lesion
M
P
Left Lung Right Lung
1
54
1
11
10
1
R
L
NOR
Q
P
RUTI Group05mm 1 lesion
05mm 3 lesions1mm 3 lesions
05mm 1 lesion1mm 2 lesions
gt2mm 1 (3mm) lesion
05mm 6 lesions1mm 20 lesions2mm 8 lesionsgt2 2 (3mm) 1 (4mm)
lesions
M
Left Lung Right Lung
35 3
6
11
05mm 1mm 2mm gt2 Coalescent
Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
INH x 4weeksbull reduced granulomabull Reduced dissemination of infectionbull Retarded evolution of granulomabullDid not induce TB specific immunity
INH x 4wks + RUTI x 2bull reduced granulomabullReduced dissemination of infectionbull Promoted evolution of granulomabull Induced TB specific immunity
(Gill O PLoS ONE 5(4) e10030 doi101371journalpone0010030)
Conclusion
bull HIV associated TB accounts for the vast majority of TB in sub-Saharan Africa
bull Need new safe short effective regimens for HIV associated TB including MXDR TB
bull Use of adjunctive immunotherapy should be evaluated
bull Need new safe short effective regimens for treating LTBI particularly for DR TB
bull Therapeutic TB vaccines required
Acknowledgements
bull Helen McIlleronbull Ann Ginsburg
- Issues in TB Drug DevelopmentTBHIV
- Presentation outline
- SA has one of the worst TB epidemics in the world
- Integrated TB and HIV treatment saves lives
- Projected use of PI-based ART
- Slide Number 6
- Effect of IPT and ART on TB incidence and mortality
- Effect of IPT and ART on TB incidence and mortality
- Reduction in TB incidence with 36 vs 6 months IPT
- Reduction in TB incidence with 36 vs 6 months IPT
- New drugs amp regimens required for HIV associated TB
- Rifapentine ndash food interactions
- Potential interactions bw fluroquinolones and antiretrovirals
- PXR regulates drug-metabolizing enzymes
- Rifampicin is a potent activator of PXR
- Drug-Drug Interactions
- Combined toxicities
- Role of adjunctive immunotherapy
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
- Supplementing effector cytokines to assist with antimicrobial activity
- Preventing HIV associated TB
- Isoniazid preventive therapy
- Slide Number 25
- LTBI with MDRXDR TB
- Slide Number 27
- Treatment of LTBI
- Slide Number 29
- Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
- Conclusion
- Acknowledgements
-
bull Thalidomide analogsndash Inhibit TNFα which is essential for granuloma
formationbull Entanercept (soluble TNF receptor)bull High dose prednisone
Concernsbull Requires concomitant bactericidal therapybull Agents inhibit protective immunity thereby
facilitating growth of organismsbull immunosuppression may result in OIs
Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
Supplementing effector cytokines to assist with antimicrobial activityRh-IFN-γ amp αRh-IL-2Rh-GM-CSFIL-12
Preventing HIV associated TB
Latent TB infection
TB disease
Treatment of latent TB infection
bull Isoniazid preventive therapy
Restore boost protective immunitybull ARTbull PrePost exposure TB vaccines
Isoniazid preventive therapy
bull Good safety profilebull Effective cheap amp readily availablebull Public health benefitBUTbull Requires a long treatment periodbull TB rates remain high in pts with advanced
HIV diseasebull Limited durabilitybull Adherence problematicbull Concern about promoting resistance
bull Efficacy compared to INH
TB incidence rate ratio (RR)minus INH (13) RR = 067minus INH + RIF (2) RR = 041minus RIF + PZA (4) RR = 054minus INH RIF + PZA (1) RR = 048
bull Increased side effects resulting in discontinuation
Multi-drug TB preventive therapyregimens
LTBI with MDRXDR TB
bull MDR TB increased globallybull Close contacts of MDRXDR TB patients are
at increased risk of becoming infectedbull PLHIV infected with MDRXDR TB are at
high risk of progressing to diseasebull Almost no data and inconsistent
international guidelines for treating contacts of MDR TB patients
HIV associated MDR amp XDR TB in SA
(N Gandhi Am J Resp Crit Care Med 2009)
Treatment of LTBIbull Effective tolerable ultra short course
treatment for DS LTBI requiredndash Mouse model of LTBI
(Eric Nuermberger) bull JgtRgtRHbull J=P=HPbull JPgtPZ
bull Effective treatment for LTBI with MDRXDR TB urgently neededndash need to evaluate regimens in mouse model
0003
006009
0003
006009
01
10
100
1000
10000
New TB cases
million in 2050
Treatment ratelatentyr
Vaccinations uninfected yr
ELIMINATING TB BY 2050BY PREVENTING INFECTION AND TREATING LATENT
INFECTIONEliminating TB by 2050Requires both PT and vaccines
M
8
L
O
Q
P
Control Group05mm 3 lesions1mm 25 lesions2mm 6 lesions
05mm 18 lesions1mm 8 lesions2mm 3 lesions
05mm 53 lesions1mm 13 lesions2mm 3 lesions
05mm 4 lesions1mm 1 lesions2mm 3 lesions
05mm 4 lesions1mm 3 lesions2mm 1 lesion
05mm 7 lesions1mm 4 lesions
05mm 24 lesions1mm 75 lesions2mm 10 lesionsgt2 2 (3mm) lesionsCoalescent 1 (4mm)
lesions R
Left Lung Right Lung
11
112
869
29
34
N
M
L
NO
Q
Qx Group05mm 1 lesion
05mm 5 lesions1mm 4 lesions2mm 1 lesion
05mm 5 lesions1mm 5 lesions2mm 1 lesion
05mm 1 lesion
1mm 1 lesion
05mm 8 lesions1mm 38 lesions2mm 2 lesionsgt2 3 (3mm) 1 (5mm)
1(6mm) lesionsCoalescent 1 (5mm) lesion
M
P
Left Lung Right Lung
1
54
1
11
10
1
R
L
NOR
Q
P
RUTI Group05mm 1 lesion
05mm 3 lesions1mm 3 lesions
05mm 1 lesion1mm 2 lesions
gt2mm 1 (3mm) lesion
05mm 6 lesions1mm 20 lesions2mm 8 lesionsgt2 2 (3mm) 1 (4mm)
lesions
M
Left Lung Right Lung
35 3
6
11
05mm 1mm 2mm gt2 Coalescent
Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
INH x 4weeksbull reduced granulomabull Reduced dissemination of infectionbull Retarded evolution of granulomabullDid not induce TB specific immunity
INH x 4wks + RUTI x 2bull reduced granulomabullReduced dissemination of infectionbull Promoted evolution of granulomabull Induced TB specific immunity
(Gill O PLoS ONE 5(4) e10030 doi101371journalpone0010030)
Conclusion
bull HIV associated TB accounts for the vast majority of TB in sub-Saharan Africa
bull Need new safe short effective regimens for HIV associated TB including MXDR TB
bull Use of adjunctive immunotherapy should be evaluated
bull Need new safe short effective regimens for treating LTBI particularly for DR TB
bull Therapeutic TB vaccines required
Acknowledgements
bull Helen McIlleronbull Ann Ginsburg
- Issues in TB Drug DevelopmentTBHIV
- Presentation outline
- SA has one of the worst TB epidemics in the world
- Integrated TB and HIV treatment saves lives
- Projected use of PI-based ART
- Slide Number 6
- Effect of IPT and ART on TB incidence and mortality
- Effect of IPT and ART on TB incidence and mortality
- Reduction in TB incidence with 36 vs 6 months IPT
- Reduction in TB incidence with 36 vs 6 months IPT
- New drugs amp regimens required for HIV associated TB
- Rifapentine ndash food interactions
- Potential interactions bw fluroquinolones and antiretrovirals
- PXR regulates drug-metabolizing enzymes
- Rifampicin is a potent activator of PXR
- Drug-Drug Interactions
- Combined toxicities
- Role of adjunctive immunotherapy
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
- Supplementing effector cytokines to assist with antimicrobial activity
- Preventing HIV associated TB
- Isoniazid preventive therapy
- Slide Number 25
- LTBI with MDRXDR TB
- Slide Number 27
- Treatment of LTBI
- Slide Number 29
- Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
- Conclusion
- Acknowledgements
-
Supplementing effector cytokines to assist with antimicrobial activityRh-IFN-γ amp αRh-IL-2Rh-GM-CSFIL-12
Preventing HIV associated TB
Latent TB infection
TB disease
Treatment of latent TB infection
bull Isoniazid preventive therapy
Restore boost protective immunitybull ARTbull PrePost exposure TB vaccines
Isoniazid preventive therapy
bull Good safety profilebull Effective cheap amp readily availablebull Public health benefitBUTbull Requires a long treatment periodbull TB rates remain high in pts with advanced
HIV diseasebull Limited durabilitybull Adherence problematicbull Concern about promoting resistance
bull Efficacy compared to INH
TB incidence rate ratio (RR)minus INH (13) RR = 067minus INH + RIF (2) RR = 041minus RIF + PZA (4) RR = 054minus INH RIF + PZA (1) RR = 048
bull Increased side effects resulting in discontinuation
Multi-drug TB preventive therapyregimens
LTBI with MDRXDR TB
bull MDR TB increased globallybull Close contacts of MDRXDR TB patients are
at increased risk of becoming infectedbull PLHIV infected with MDRXDR TB are at
high risk of progressing to diseasebull Almost no data and inconsistent
international guidelines for treating contacts of MDR TB patients
HIV associated MDR amp XDR TB in SA
(N Gandhi Am J Resp Crit Care Med 2009)
Treatment of LTBIbull Effective tolerable ultra short course
treatment for DS LTBI requiredndash Mouse model of LTBI
(Eric Nuermberger) bull JgtRgtRHbull J=P=HPbull JPgtPZ
bull Effective treatment for LTBI with MDRXDR TB urgently neededndash need to evaluate regimens in mouse model
0003
006009
0003
006009
01
10
100
1000
10000
New TB cases
million in 2050
Treatment ratelatentyr
Vaccinations uninfected yr
ELIMINATING TB BY 2050BY PREVENTING INFECTION AND TREATING LATENT
INFECTIONEliminating TB by 2050Requires both PT and vaccines
M
8
L
O
Q
P
Control Group05mm 3 lesions1mm 25 lesions2mm 6 lesions
05mm 18 lesions1mm 8 lesions2mm 3 lesions
05mm 53 lesions1mm 13 lesions2mm 3 lesions
05mm 4 lesions1mm 1 lesions2mm 3 lesions
05mm 4 lesions1mm 3 lesions2mm 1 lesion
05mm 7 lesions1mm 4 lesions
05mm 24 lesions1mm 75 lesions2mm 10 lesionsgt2 2 (3mm) lesionsCoalescent 1 (4mm)
lesions R
Left Lung Right Lung
11
112
869
29
34
N
M
L
NO
Q
Qx Group05mm 1 lesion
05mm 5 lesions1mm 4 lesions2mm 1 lesion
05mm 5 lesions1mm 5 lesions2mm 1 lesion
05mm 1 lesion
1mm 1 lesion
05mm 8 lesions1mm 38 lesions2mm 2 lesionsgt2 3 (3mm) 1 (5mm)
1(6mm) lesionsCoalescent 1 (5mm) lesion
M
P
Left Lung Right Lung
1
54
1
11
10
1
R
L
NOR
Q
P
RUTI Group05mm 1 lesion
05mm 3 lesions1mm 3 lesions
05mm 1 lesion1mm 2 lesions
gt2mm 1 (3mm) lesion
05mm 6 lesions1mm 20 lesions2mm 8 lesionsgt2 2 (3mm) 1 (4mm)
lesions
M
Left Lung Right Lung
35 3
6
11
05mm 1mm 2mm gt2 Coalescent
Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
INH x 4weeksbull reduced granulomabull Reduced dissemination of infectionbull Retarded evolution of granulomabullDid not induce TB specific immunity
INH x 4wks + RUTI x 2bull reduced granulomabullReduced dissemination of infectionbull Promoted evolution of granulomabull Induced TB specific immunity
(Gill O PLoS ONE 5(4) e10030 doi101371journalpone0010030)
Conclusion
bull HIV associated TB accounts for the vast majority of TB in sub-Saharan Africa
bull Need new safe short effective regimens for HIV associated TB including MXDR TB
bull Use of adjunctive immunotherapy should be evaluated
bull Need new safe short effective regimens for treating LTBI particularly for DR TB
bull Therapeutic TB vaccines required
Acknowledgements
bull Helen McIlleronbull Ann Ginsburg
- Issues in TB Drug DevelopmentTBHIV
- Presentation outline
- SA has one of the worst TB epidemics in the world
- Integrated TB and HIV treatment saves lives
- Projected use of PI-based ART
- Slide Number 6
- Effect of IPT and ART on TB incidence and mortality
- Effect of IPT and ART on TB incidence and mortality
- Reduction in TB incidence with 36 vs 6 months IPT
- Reduction in TB incidence with 36 vs 6 months IPT
- New drugs amp regimens required for HIV associated TB
- Rifapentine ndash food interactions
- Potential interactions bw fluroquinolones and antiretrovirals
- PXR regulates drug-metabolizing enzymes
- Rifampicin is a potent activator of PXR
- Drug-Drug Interactions
- Combined toxicities
- Role of adjunctive immunotherapy
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
- Supplementing effector cytokines to assist with antimicrobial activity
- Preventing HIV associated TB
- Isoniazid preventive therapy
- Slide Number 25
- LTBI with MDRXDR TB
- Slide Number 27
- Treatment of LTBI
- Slide Number 29
- Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
- Conclusion
- Acknowledgements
-
Preventing HIV associated TB
Latent TB infection
TB disease
Treatment of latent TB infection
bull Isoniazid preventive therapy
Restore boost protective immunitybull ARTbull PrePost exposure TB vaccines
Isoniazid preventive therapy
bull Good safety profilebull Effective cheap amp readily availablebull Public health benefitBUTbull Requires a long treatment periodbull TB rates remain high in pts with advanced
HIV diseasebull Limited durabilitybull Adherence problematicbull Concern about promoting resistance
bull Efficacy compared to INH
TB incidence rate ratio (RR)minus INH (13) RR = 067minus INH + RIF (2) RR = 041minus RIF + PZA (4) RR = 054minus INH RIF + PZA (1) RR = 048
bull Increased side effects resulting in discontinuation
Multi-drug TB preventive therapyregimens
LTBI with MDRXDR TB
bull MDR TB increased globallybull Close contacts of MDRXDR TB patients are
at increased risk of becoming infectedbull PLHIV infected with MDRXDR TB are at
high risk of progressing to diseasebull Almost no data and inconsistent
international guidelines for treating contacts of MDR TB patients
HIV associated MDR amp XDR TB in SA
(N Gandhi Am J Resp Crit Care Med 2009)
Treatment of LTBIbull Effective tolerable ultra short course
treatment for DS LTBI requiredndash Mouse model of LTBI
(Eric Nuermberger) bull JgtRgtRHbull J=P=HPbull JPgtPZ
bull Effective treatment for LTBI with MDRXDR TB urgently neededndash need to evaluate regimens in mouse model
0003
006009
0003
006009
01
10
100
1000
10000
New TB cases
million in 2050
Treatment ratelatentyr
Vaccinations uninfected yr
ELIMINATING TB BY 2050BY PREVENTING INFECTION AND TREATING LATENT
INFECTIONEliminating TB by 2050Requires both PT and vaccines
M
8
L
O
Q
P
Control Group05mm 3 lesions1mm 25 lesions2mm 6 lesions
05mm 18 lesions1mm 8 lesions2mm 3 lesions
05mm 53 lesions1mm 13 lesions2mm 3 lesions
05mm 4 lesions1mm 1 lesions2mm 3 lesions
05mm 4 lesions1mm 3 lesions2mm 1 lesion
05mm 7 lesions1mm 4 lesions
05mm 24 lesions1mm 75 lesions2mm 10 lesionsgt2 2 (3mm) lesionsCoalescent 1 (4mm)
lesions R
Left Lung Right Lung
11
112
869
29
34
N
M
L
NO
Q
Qx Group05mm 1 lesion
05mm 5 lesions1mm 4 lesions2mm 1 lesion
05mm 5 lesions1mm 5 lesions2mm 1 lesion
05mm 1 lesion
1mm 1 lesion
05mm 8 lesions1mm 38 lesions2mm 2 lesionsgt2 3 (3mm) 1 (5mm)
1(6mm) lesionsCoalescent 1 (5mm) lesion
M
P
Left Lung Right Lung
1
54
1
11
10
1
R
L
NOR
Q
P
RUTI Group05mm 1 lesion
05mm 3 lesions1mm 3 lesions
05mm 1 lesion1mm 2 lesions
gt2mm 1 (3mm) lesion
05mm 6 lesions1mm 20 lesions2mm 8 lesionsgt2 2 (3mm) 1 (4mm)
lesions
M
Left Lung Right Lung
35 3
6
11
05mm 1mm 2mm gt2 Coalescent
Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
INH x 4weeksbull reduced granulomabull Reduced dissemination of infectionbull Retarded evolution of granulomabullDid not induce TB specific immunity
INH x 4wks + RUTI x 2bull reduced granulomabullReduced dissemination of infectionbull Promoted evolution of granulomabull Induced TB specific immunity
(Gill O PLoS ONE 5(4) e10030 doi101371journalpone0010030)
Conclusion
bull HIV associated TB accounts for the vast majority of TB in sub-Saharan Africa
bull Need new safe short effective regimens for HIV associated TB including MXDR TB
bull Use of adjunctive immunotherapy should be evaluated
bull Need new safe short effective regimens for treating LTBI particularly for DR TB
bull Therapeutic TB vaccines required
Acknowledgements
bull Helen McIlleronbull Ann Ginsburg
- Issues in TB Drug DevelopmentTBHIV
- Presentation outline
- SA has one of the worst TB epidemics in the world
- Integrated TB and HIV treatment saves lives
- Projected use of PI-based ART
- Slide Number 6
- Effect of IPT and ART on TB incidence and mortality
- Effect of IPT and ART on TB incidence and mortality
- Reduction in TB incidence with 36 vs 6 months IPT
- Reduction in TB incidence with 36 vs 6 months IPT
- New drugs amp regimens required for HIV associated TB
- Rifapentine ndash food interactions
- Potential interactions bw fluroquinolones and antiretrovirals
- PXR regulates drug-metabolizing enzymes
- Rifampicin is a potent activator of PXR
- Drug-Drug Interactions
- Combined toxicities
- Role of adjunctive immunotherapy
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
- Supplementing effector cytokines to assist with antimicrobial activity
- Preventing HIV associated TB
- Isoniazid preventive therapy
- Slide Number 25
- LTBI with MDRXDR TB
- Slide Number 27
- Treatment of LTBI
- Slide Number 29
- Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
- Conclusion
- Acknowledgements
-
Isoniazid preventive therapy
bull Good safety profilebull Effective cheap amp readily availablebull Public health benefitBUTbull Requires a long treatment periodbull TB rates remain high in pts with advanced
HIV diseasebull Limited durabilitybull Adherence problematicbull Concern about promoting resistance
bull Efficacy compared to INH
TB incidence rate ratio (RR)minus INH (13) RR = 067minus INH + RIF (2) RR = 041minus RIF + PZA (4) RR = 054minus INH RIF + PZA (1) RR = 048
bull Increased side effects resulting in discontinuation
Multi-drug TB preventive therapyregimens
LTBI with MDRXDR TB
bull MDR TB increased globallybull Close contacts of MDRXDR TB patients are
at increased risk of becoming infectedbull PLHIV infected with MDRXDR TB are at
high risk of progressing to diseasebull Almost no data and inconsistent
international guidelines for treating contacts of MDR TB patients
HIV associated MDR amp XDR TB in SA
(N Gandhi Am J Resp Crit Care Med 2009)
Treatment of LTBIbull Effective tolerable ultra short course
treatment for DS LTBI requiredndash Mouse model of LTBI
(Eric Nuermberger) bull JgtRgtRHbull J=P=HPbull JPgtPZ
bull Effective treatment for LTBI with MDRXDR TB urgently neededndash need to evaluate regimens in mouse model
0003
006009
0003
006009
01
10
100
1000
10000
New TB cases
million in 2050
Treatment ratelatentyr
Vaccinations uninfected yr
ELIMINATING TB BY 2050BY PREVENTING INFECTION AND TREATING LATENT
INFECTIONEliminating TB by 2050Requires both PT and vaccines
M
8
L
O
Q
P
Control Group05mm 3 lesions1mm 25 lesions2mm 6 lesions
05mm 18 lesions1mm 8 lesions2mm 3 lesions
05mm 53 lesions1mm 13 lesions2mm 3 lesions
05mm 4 lesions1mm 1 lesions2mm 3 lesions
05mm 4 lesions1mm 3 lesions2mm 1 lesion
05mm 7 lesions1mm 4 lesions
05mm 24 lesions1mm 75 lesions2mm 10 lesionsgt2 2 (3mm) lesionsCoalescent 1 (4mm)
lesions R
Left Lung Right Lung
11
112
869
29
34
N
M
L
NO
Q
Qx Group05mm 1 lesion
05mm 5 lesions1mm 4 lesions2mm 1 lesion
05mm 5 lesions1mm 5 lesions2mm 1 lesion
05mm 1 lesion
1mm 1 lesion
05mm 8 lesions1mm 38 lesions2mm 2 lesionsgt2 3 (3mm) 1 (5mm)
1(6mm) lesionsCoalescent 1 (5mm) lesion
M
P
Left Lung Right Lung
1
54
1
11
10
1
R
L
NOR
Q
P
RUTI Group05mm 1 lesion
05mm 3 lesions1mm 3 lesions
05mm 1 lesion1mm 2 lesions
gt2mm 1 (3mm) lesion
05mm 6 lesions1mm 20 lesions2mm 8 lesionsgt2 2 (3mm) 1 (4mm)
lesions
M
Left Lung Right Lung
35 3
6
11
05mm 1mm 2mm gt2 Coalescent
Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
INH x 4weeksbull reduced granulomabull Reduced dissemination of infectionbull Retarded evolution of granulomabullDid not induce TB specific immunity
INH x 4wks + RUTI x 2bull reduced granulomabullReduced dissemination of infectionbull Promoted evolution of granulomabull Induced TB specific immunity
(Gill O PLoS ONE 5(4) e10030 doi101371journalpone0010030)
Conclusion
bull HIV associated TB accounts for the vast majority of TB in sub-Saharan Africa
bull Need new safe short effective regimens for HIV associated TB including MXDR TB
bull Use of adjunctive immunotherapy should be evaluated
bull Need new safe short effective regimens for treating LTBI particularly for DR TB
bull Therapeutic TB vaccines required
Acknowledgements
bull Helen McIlleronbull Ann Ginsburg
- Issues in TB Drug DevelopmentTBHIV
- Presentation outline
- SA has one of the worst TB epidemics in the world
- Integrated TB and HIV treatment saves lives
- Projected use of PI-based ART
- Slide Number 6
- Effect of IPT and ART on TB incidence and mortality
- Effect of IPT and ART on TB incidence and mortality
- Reduction in TB incidence with 36 vs 6 months IPT
- Reduction in TB incidence with 36 vs 6 months IPT
- New drugs amp regimens required for HIV associated TB
- Rifapentine ndash food interactions
- Potential interactions bw fluroquinolones and antiretrovirals
- PXR regulates drug-metabolizing enzymes
- Rifampicin is a potent activator of PXR
- Drug-Drug Interactions
- Combined toxicities
- Role of adjunctive immunotherapy
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
- Supplementing effector cytokines to assist with antimicrobial activity
- Preventing HIV associated TB
- Isoniazid preventive therapy
- Slide Number 25
- LTBI with MDRXDR TB
- Slide Number 27
- Treatment of LTBI
- Slide Number 29
- Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
- Conclusion
- Acknowledgements
-
bull Efficacy compared to INH
TB incidence rate ratio (RR)minus INH (13) RR = 067minus INH + RIF (2) RR = 041minus RIF + PZA (4) RR = 054minus INH RIF + PZA (1) RR = 048
bull Increased side effects resulting in discontinuation
Multi-drug TB preventive therapyregimens
LTBI with MDRXDR TB
bull MDR TB increased globallybull Close contacts of MDRXDR TB patients are
at increased risk of becoming infectedbull PLHIV infected with MDRXDR TB are at
high risk of progressing to diseasebull Almost no data and inconsistent
international guidelines for treating contacts of MDR TB patients
HIV associated MDR amp XDR TB in SA
(N Gandhi Am J Resp Crit Care Med 2009)
Treatment of LTBIbull Effective tolerable ultra short course
treatment for DS LTBI requiredndash Mouse model of LTBI
(Eric Nuermberger) bull JgtRgtRHbull J=P=HPbull JPgtPZ
bull Effective treatment for LTBI with MDRXDR TB urgently neededndash need to evaluate regimens in mouse model
0003
006009
0003
006009
01
10
100
1000
10000
New TB cases
million in 2050
Treatment ratelatentyr
Vaccinations uninfected yr
ELIMINATING TB BY 2050BY PREVENTING INFECTION AND TREATING LATENT
INFECTIONEliminating TB by 2050Requires both PT and vaccines
M
8
L
O
Q
P
Control Group05mm 3 lesions1mm 25 lesions2mm 6 lesions
05mm 18 lesions1mm 8 lesions2mm 3 lesions
05mm 53 lesions1mm 13 lesions2mm 3 lesions
05mm 4 lesions1mm 1 lesions2mm 3 lesions
05mm 4 lesions1mm 3 lesions2mm 1 lesion
05mm 7 lesions1mm 4 lesions
05mm 24 lesions1mm 75 lesions2mm 10 lesionsgt2 2 (3mm) lesionsCoalescent 1 (4mm)
lesions R
Left Lung Right Lung
11
112
869
29
34
N
M
L
NO
Q
Qx Group05mm 1 lesion
05mm 5 lesions1mm 4 lesions2mm 1 lesion
05mm 5 lesions1mm 5 lesions2mm 1 lesion
05mm 1 lesion
1mm 1 lesion
05mm 8 lesions1mm 38 lesions2mm 2 lesionsgt2 3 (3mm) 1 (5mm)
1(6mm) lesionsCoalescent 1 (5mm) lesion
M
P
Left Lung Right Lung
1
54
1
11
10
1
R
L
NOR
Q
P
RUTI Group05mm 1 lesion
05mm 3 lesions1mm 3 lesions
05mm 1 lesion1mm 2 lesions
gt2mm 1 (3mm) lesion
05mm 6 lesions1mm 20 lesions2mm 8 lesionsgt2 2 (3mm) 1 (4mm)
lesions
M
Left Lung Right Lung
35 3
6
11
05mm 1mm 2mm gt2 Coalescent
Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
INH x 4weeksbull reduced granulomabull Reduced dissemination of infectionbull Retarded evolution of granulomabullDid not induce TB specific immunity
INH x 4wks + RUTI x 2bull reduced granulomabullReduced dissemination of infectionbull Promoted evolution of granulomabull Induced TB specific immunity
(Gill O PLoS ONE 5(4) e10030 doi101371journalpone0010030)
Conclusion
bull HIV associated TB accounts for the vast majority of TB in sub-Saharan Africa
bull Need new safe short effective regimens for HIV associated TB including MXDR TB
bull Use of adjunctive immunotherapy should be evaluated
bull Need new safe short effective regimens for treating LTBI particularly for DR TB
bull Therapeutic TB vaccines required
Acknowledgements
bull Helen McIlleronbull Ann Ginsburg
- Issues in TB Drug DevelopmentTBHIV
- Presentation outline
- SA has one of the worst TB epidemics in the world
- Integrated TB and HIV treatment saves lives
- Projected use of PI-based ART
- Slide Number 6
- Effect of IPT and ART on TB incidence and mortality
- Effect of IPT and ART on TB incidence and mortality
- Reduction in TB incidence with 36 vs 6 months IPT
- Reduction in TB incidence with 36 vs 6 months IPT
- New drugs amp regimens required for HIV associated TB
- Rifapentine ndash food interactions
- Potential interactions bw fluroquinolones and antiretrovirals
- PXR regulates drug-metabolizing enzymes
- Rifampicin is a potent activator of PXR
- Drug-Drug Interactions
- Combined toxicities
- Role of adjunctive immunotherapy
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
- Supplementing effector cytokines to assist with antimicrobial activity
- Preventing HIV associated TB
- Isoniazid preventive therapy
- Slide Number 25
- LTBI with MDRXDR TB
- Slide Number 27
- Treatment of LTBI
- Slide Number 29
- Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
- Conclusion
- Acknowledgements
-
LTBI with MDRXDR TB
bull MDR TB increased globallybull Close contacts of MDRXDR TB patients are
at increased risk of becoming infectedbull PLHIV infected with MDRXDR TB are at
high risk of progressing to diseasebull Almost no data and inconsistent
international guidelines for treating contacts of MDR TB patients
HIV associated MDR amp XDR TB in SA
(N Gandhi Am J Resp Crit Care Med 2009)
Treatment of LTBIbull Effective tolerable ultra short course
treatment for DS LTBI requiredndash Mouse model of LTBI
(Eric Nuermberger) bull JgtRgtRHbull J=P=HPbull JPgtPZ
bull Effective treatment for LTBI with MDRXDR TB urgently neededndash need to evaluate regimens in mouse model
0003
006009
0003
006009
01
10
100
1000
10000
New TB cases
million in 2050
Treatment ratelatentyr
Vaccinations uninfected yr
ELIMINATING TB BY 2050BY PREVENTING INFECTION AND TREATING LATENT
INFECTIONEliminating TB by 2050Requires both PT and vaccines
M
8
L
O
Q
P
Control Group05mm 3 lesions1mm 25 lesions2mm 6 lesions
05mm 18 lesions1mm 8 lesions2mm 3 lesions
05mm 53 lesions1mm 13 lesions2mm 3 lesions
05mm 4 lesions1mm 1 lesions2mm 3 lesions
05mm 4 lesions1mm 3 lesions2mm 1 lesion
05mm 7 lesions1mm 4 lesions
05mm 24 lesions1mm 75 lesions2mm 10 lesionsgt2 2 (3mm) lesionsCoalescent 1 (4mm)
lesions R
Left Lung Right Lung
11
112
869
29
34
N
M
L
NO
Q
Qx Group05mm 1 lesion
05mm 5 lesions1mm 4 lesions2mm 1 lesion
05mm 5 lesions1mm 5 lesions2mm 1 lesion
05mm 1 lesion
1mm 1 lesion
05mm 8 lesions1mm 38 lesions2mm 2 lesionsgt2 3 (3mm) 1 (5mm)
1(6mm) lesionsCoalescent 1 (5mm) lesion
M
P
Left Lung Right Lung
1
54
1
11
10
1
R
L
NOR
Q
P
RUTI Group05mm 1 lesion
05mm 3 lesions1mm 3 lesions
05mm 1 lesion1mm 2 lesions
gt2mm 1 (3mm) lesion
05mm 6 lesions1mm 20 lesions2mm 8 lesionsgt2 2 (3mm) 1 (4mm)
lesions
M
Left Lung Right Lung
35 3
6
11
05mm 1mm 2mm gt2 Coalescent
Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
INH x 4weeksbull reduced granulomabull Reduced dissemination of infectionbull Retarded evolution of granulomabullDid not induce TB specific immunity
INH x 4wks + RUTI x 2bull reduced granulomabullReduced dissemination of infectionbull Promoted evolution of granulomabull Induced TB specific immunity
(Gill O PLoS ONE 5(4) e10030 doi101371journalpone0010030)
Conclusion
bull HIV associated TB accounts for the vast majority of TB in sub-Saharan Africa
bull Need new safe short effective regimens for HIV associated TB including MXDR TB
bull Use of adjunctive immunotherapy should be evaluated
bull Need new safe short effective regimens for treating LTBI particularly for DR TB
bull Therapeutic TB vaccines required
Acknowledgements
bull Helen McIlleronbull Ann Ginsburg
- Issues in TB Drug DevelopmentTBHIV
- Presentation outline
- SA has one of the worst TB epidemics in the world
- Integrated TB and HIV treatment saves lives
- Projected use of PI-based ART
- Slide Number 6
- Effect of IPT and ART on TB incidence and mortality
- Effect of IPT and ART on TB incidence and mortality
- Reduction in TB incidence with 36 vs 6 months IPT
- Reduction in TB incidence with 36 vs 6 months IPT
- New drugs amp regimens required for HIV associated TB
- Rifapentine ndash food interactions
- Potential interactions bw fluroquinolones and antiretrovirals
- PXR regulates drug-metabolizing enzymes
- Rifampicin is a potent activator of PXR
- Drug-Drug Interactions
- Combined toxicities
- Role of adjunctive immunotherapy
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
- Supplementing effector cytokines to assist with antimicrobial activity
- Preventing HIV associated TB
- Isoniazid preventive therapy
- Slide Number 25
- LTBI with MDRXDR TB
- Slide Number 27
- Treatment of LTBI
- Slide Number 29
- Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
- Conclusion
- Acknowledgements
-
HIV associated MDR amp XDR TB in SA
(N Gandhi Am J Resp Crit Care Med 2009)
Treatment of LTBIbull Effective tolerable ultra short course
treatment for DS LTBI requiredndash Mouse model of LTBI
(Eric Nuermberger) bull JgtRgtRHbull J=P=HPbull JPgtPZ
bull Effective treatment for LTBI with MDRXDR TB urgently neededndash need to evaluate regimens in mouse model
0003
006009
0003
006009
01
10
100
1000
10000
New TB cases
million in 2050
Treatment ratelatentyr
Vaccinations uninfected yr
ELIMINATING TB BY 2050BY PREVENTING INFECTION AND TREATING LATENT
INFECTIONEliminating TB by 2050Requires both PT and vaccines
M
8
L
O
Q
P
Control Group05mm 3 lesions1mm 25 lesions2mm 6 lesions
05mm 18 lesions1mm 8 lesions2mm 3 lesions
05mm 53 lesions1mm 13 lesions2mm 3 lesions
05mm 4 lesions1mm 1 lesions2mm 3 lesions
05mm 4 lesions1mm 3 lesions2mm 1 lesion
05mm 7 lesions1mm 4 lesions
05mm 24 lesions1mm 75 lesions2mm 10 lesionsgt2 2 (3mm) lesionsCoalescent 1 (4mm)
lesions R
Left Lung Right Lung
11
112
869
29
34
N
M
L
NO
Q
Qx Group05mm 1 lesion
05mm 5 lesions1mm 4 lesions2mm 1 lesion
05mm 5 lesions1mm 5 lesions2mm 1 lesion
05mm 1 lesion
1mm 1 lesion
05mm 8 lesions1mm 38 lesions2mm 2 lesionsgt2 3 (3mm) 1 (5mm)
1(6mm) lesionsCoalescent 1 (5mm) lesion
M
P
Left Lung Right Lung
1
54
1
11
10
1
R
L
NOR
Q
P
RUTI Group05mm 1 lesion
05mm 3 lesions1mm 3 lesions
05mm 1 lesion1mm 2 lesions
gt2mm 1 (3mm) lesion
05mm 6 lesions1mm 20 lesions2mm 8 lesionsgt2 2 (3mm) 1 (4mm)
lesions
M
Left Lung Right Lung
35 3
6
11
05mm 1mm 2mm gt2 Coalescent
Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
INH x 4weeksbull reduced granulomabull Reduced dissemination of infectionbull Retarded evolution of granulomabullDid not induce TB specific immunity
INH x 4wks + RUTI x 2bull reduced granulomabullReduced dissemination of infectionbull Promoted evolution of granulomabull Induced TB specific immunity
(Gill O PLoS ONE 5(4) e10030 doi101371journalpone0010030)
Conclusion
bull HIV associated TB accounts for the vast majority of TB in sub-Saharan Africa
bull Need new safe short effective regimens for HIV associated TB including MXDR TB
bull Use of adjunctive immunotherapy should be evaluated
bull Need new safe short effective regimens for treating LTBI particularly for DR TB
bull Therapeutic TB vaccines required
Acknowledgements
bull Helen McIlleronbull Ann Ginsburg
- Issues in TB Drug DevelopmentTBHIV
- Presentation outline
- SA has one of the worst TB epidemics in the world
- Integrated TB and HIV treatment saves lives
- Projected use of PI-based ART
- Slide Number 6
- Effect of IPT and ART on TB incidence and mortality
- Effect of IPT and ART on TB incidence and mortality
- Reduction in TB incidence with 36 vs 6 months IPT
- Reduction in TB incidence with 36 vs 6 months IPT
- New drugs amp regimens required for HIV associated TB
- Rifapentine ndash food interactions
- Potential interactions bw fluroquinolones and antiretrovirals
- PXR regulates drug-metabolizing enzymes
- Rifampicin is a potent activator of PXR
- Drug-Drug Interactions
- Combined toxicities
- Role of adjunctive immunotherapy
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
- Supplementing effector cytokines to assist with antimicrobial activity
- Preventing HIV associated TB
- Isoniazid preventive therapy
- Slide Number 25
- LTBI with MDRXDR TB
- Slide Number 27
- Treatment of LTBI
- Slide Number 29
- Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
- Conclusion
- Acknowledgements
-
Treatment of LTBIbull Effective tolerable ultra short course
treatment for DS LTBI requiredndash Mouse model of LTBI
(Eric Nuermberger) bull JgtRgtRHbull J=P=HPbull JPgtPZ
bull Effective treatment for LTBI with MDRXDR TB urgently neededndash need to evaluate regimens in mouse model
0003
006009
0003
006009
01
10
100
1000
10000
New TB cases
million in 2050
Treatment ratelatentyr
Vaccinations uninfected yr
ELIMINATING TB BY 2050BY PREVENTING INFECTION AND TREATING LATENT
INFECTIONEliminating TB by 2050Requires both PT and vaccines
M
8
L
O
Q
P
Control Group05mm 3 lesions1mm 25 lesions2mm 6 lesions
05mm 18 lesions1mm 8 lesions2mm 3 lesions
05mm 53 lesions1mm 13 lesions2mm 3 lesions
05mm 4 lesions1mm 1 lesions2mm 3 lesions
05mm 4 lesions1mm 3 lesions2mm 1 lesion
05mm 7 lesions1mm 4 lesions
05mm 24 lesions1mm 75 lesions2mm 10 lesionsgt2 2 (3mm) lesionsCoalescent 1 (4mm)
lesions R
Left Lung Right Lung
11
112
869
29
34
N
M
L
NO
Q
Qx Group05mm 1 lesion
05mm 5 lesions1mm 4 lesions2mm 1 lesion
05mm 5 lesions1mm 5 lesions2mm 1 lesion
05mm 1 lesion
1mm 1 lesion
05mm 8 lesions1mm 38 lesions2mm 2 lesionsgt2 3 (3mm) 1 (5mm)
1(6mm) lesionsCoalescent 1 (5mm) lesion
M
P
Left Lung Right Lung
1
54
1
11
10
1
R
L
NOR
Q
P
RUTI Group05mm 1 lesion
05mm 3 lesions1mm 3 lesions
05mm 1 lesion1mm 2 lesions
gt2mm 1 (3mm) lesion
05mm 6 lesions1mm 20 lesions2mm 8 lesionsgt2 2 (3mm) 1 (4mm)
lesions
M
Left Lung Right Lung
35 3
6
11
05mm 1mm 2mm gt2 Coalescent
Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
INH x 4weeksbull reduced granulomabull Reduced dissemination of infectionbull Retarded evolution of granulomabullDid not induce TB specific immunity
INH x 4wks + RUTI x 2bull reduced granulomabullReduced dissemination of infectionbull Promoted evolution of granulomabull Induced TB specific immunity
(Gill O PLoS ONE 5(4) e10030 doi101371journalpone0010030)
Conclusion
bull HIV associated TB accounts for the vast majority of TB in sub-Saharan Africa
bull Need new safe short effective regimens for HIV associated TB including MXDR TB
bull Use of adjunctive immunotherapy should be evaluated
bull Need new safe short effective regimens for treating LTBI particularly for DR TB
bull Therapeutic TB vaccines required
Acknowledgements
bull Helen McIlleronbull Ann Ginsburg
- Issues in TB Drug DevelopmentTBHIV
- Presentation outline
- SA has one of the worst TB epidemics in the world
- Integrated TB and HIV treatment saves lives
- Projected use of PI-based ART
- Slide Number 6
- Effect of IPT and ART on TB incidence and mortality
- Effect of IPT and ART on TB incidence and mortality
- Reduction in TB incidence with 36 vs 6 months IPT
- Reduction in TB incidence with 36 vs 6 months IPT
- New drugs amp regimens required for HIV associated TB
- Rifapentine ndash food interactions
- Potential interactions bw fluroquinolones and antiretrovirals
- PXR regulates drug-metabolizing enzymes
- Rifampicin is a potent activator of PXR
- Drug-Drug Interactions
- Combined toxicities
- Role of adjunctive immunotherapy
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
- Supplementing effector cytokines to assist with antimicrobial activity
- Preventing HIV associated TB
- Isoniazid preventive therapy
- Slide Number 25
- LTBI with MDRXDR TB
- Slide Number 27
- Treatment of LTBI
- Slide Number 29
- Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
- Conclusion
- Acknowledgements
-
0003
006009
0003
006009
01
10
100
1000
10000
New TB cases
million in 2050
Treatment ratelatentyr
Vaccinations uninfected yr
ELIMINATING TB BY 2050BY PREVENTING INFECTION AND TREATING LATENT
INFECTIONEliminating TB by 2050Requires both PT and vaccines
M
8
L
O
Q
P
Control Group05mm 3 lesions1mm 25 lesions2mm 6 lesions
05mm 18 lesions1mm 8 lesions2mm 3 lesions
05mm 53 lesions1mm 13 lesions2mm 3 lesions
05mm 4 lesions1mm 1 lesions2mm 3 lesions
05mm 4 lesions1mm 3 lesions2mm 1 lesion
05mm 7 lesions1mm 4 lesions
05mm 24 lesions1mm 75 lesions2mm 10 lesionsgt2 2 (3mm) lesionsCoalescent 1 (4mm)
lesions R
Left Lung Right Lung
11
112
869
29
34
N
M
L
NO
Q
Qx Group05mm 1 lesion
05mm 5 lesions1mm 4 lesions2mm 1 lesion
05mm 5 lesions1mm 5 lesions2mm 1 lesion
05mm 1 lesion
1mm 1 lesion
05mm 8 lesions1mm 38 lesions2mm 2 lesionsgt2 3 (3mm) 1 (5mm)
1(6mm) lesionsCoalescent 1 (5mm) lesion
M
P
Left Lung Right Lung
1
54
1
11
10
1
R
L
NOR
Q
P
RUTI Group05mm 1 lesion
05mm 3 lesions1mm 3 lesions
05mm 1 lesion1mm 2 lesions
gt2mm 1 (3mm) lesion
05mm 6 lesions1mm 20 lesions2mm 8 lesionsgt2 2 (3mm) 1 (4mm)
lesions
M
Left Lung Right Lung
35 3
6
11
05mm 1mm 2mm gt2 Coalescent
Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
INH x 4weeksbull reduced granulomabull Reduced dissemination of infectionbull Retarded evolution of granulomabullDid not induce TB specific immunity
INH x 4wks + RUTI x 2bull reduced granulomabullReduced dissemination of infectionbull Promoted evolution of granulomabull Induced TB specific immunity
(Gill O PLoS ONE 5(4) e10030 doi101371journalpone0010030)
Conclusion
bull HIV associated TB accounts for the vast majority of TB in sub-Saharan Africa
bull Need new safe short effective regimens for HIV associated TB including MXDR TB
bull Use of adjunctive immunotherapy should be evaluated
bull Need new safe short effective regimens for treating LTBI particularly for DR TB
bull Therapeutic TB vaccines required
Acknowledgements
bull Helen McIlleronbull Ann Ginsburg
- Issues in TB Drug DevelopmentTBHIV
- Presentation outline
- SA has one of the worst TB epidemics in the world
- Integrated TB and HIV treatment saves lives
- Projected use of PI-based ART
- Slide Number 6
- Effect of IPT and ART on TB incidence and mortality
- Effect of IPT and ART on TB incidence and mortality
- Reduction in TB incidence with 36 vs 6 months IPT
- Reduction in TB incidence with 36 vs 6 months IPT
- New drugs amp regimens required for HIV associated TB
- Rifapentine ndash food interactions
- Potential interactions bw fluroquinolones and antiretrovirals
- PXR regulates drug-metabolizing enzymes
- Rifampicin is a potent activator of PXR
- Drug-Drug Interactions
- Combined toxicities
- Role of adjunctive immunotherapy
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
- Supplementing effector cytokines to assist with antimicrobial activity
- Preventing HIV associated TB
- Isoniazid preventive therapy
- Slide Number 25
- LTBI with MDRXDR TB
- Slide Number 27
- Treatment of LTBI
- Slide Number 29
- Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
- Conclusion
- Acknowledgements
-
M
8
L
O
Q
P
Control Group05mm 3 lesions1mm 25 lesions2mm 6 lesions
05mm 18 lesions1mm 8 lesions2mm 3 lesions
05mm 53 lesions1mm 13 lesions2mm 3 lesions
05mm 4 lesions1mm 1 lesions2mm 3 lesions
05mm 4 lesions1mm 3 lesions2mm 1 lesion
05mm 7 lesions1mm 4 lesions
05mm 24 lesions1mm 75 lesions2mm 10 lesionsgt2 2 (3mm) lesionsCoalescent 1 (4mm)
lesions R
Left Lung Right Lung
11
112
869
29
34
N
M
L
NO
Q
Qx Group05mm 1 lesion
05mm 5 lesions1mm 4 lesions2mm 1 lesion
05mm 5 lesions1mm 5 lesions2mm 1 lesion
05mm 1 lesion
1mm 1 lesion
05mm 8 lesions1mm 38 lesions2mm 2 lesionsgt2 3 (3mm) 1 (5mm)
1(6mm) lesionsCoalescent 1 (5mm) lesion
M
P
Left Lung Right Lung
1
54
1
11
10
1
R
L
NOR
Q
P
RUTI Group05mm 1 lesion
05mm 3 lesions1mm 3 lesions
05mm 1 lesion1mm 2 lesions
gt2mm 1 (3mm) lesion
05mm 6 lesions1mm 20 lesions2mm 8 lesionsgt2 2 (3mm) 1 (4mm)
lesions
M
Left Lung Right Lung
35 3
6
11
05mm 1mm 2mm gt2 Coalescent
Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
INH x 4weeksbull reduced granulomabull Reduced dissemination of infectionbull Retarded evolution of granulomabullDid not induce TB specific immunity
INH x 4wks + RUTI x 2bull reduced granulomabullReduced dissemination of infectionbull Promoted evolution of granulomabull Induced TB specific immunity
(Gill O PLoS ONE 5(4) e10030 doi101371journalpone0010030)
Conclusion
bull HIV associated TB accounts for the vast majority of TB in sub-Saharan Africa
bull Need new safe short effective regimens for HIV associated TB including MXDR TB
bull Use of adjunctive immunotherapy should be evaluated
bull Need new safe short effective regimens for treating LTBI particularly for DR TB
bull Therapeutic TB vaccines required
Acknowledgements
bull Helen McIlleronbull Ann Ginsburg
- Issues in TB Drug DevelopmentTBHIV
- Presentation outline
- SA has one of the worst TB epidemics in the world
- Integrated TB and HIV treatment saves lives
- Projected use of PI-based ART
- Slide Number 6
- Effect of IPT and ART on TB incidence and mortality
- Effect of IPT and ART on TB incidence and mortality
- Reduction in TB incidence with 36 vs 6 months IPT
- Reduction in TB incidence with 36 vs 6 months IPT
- New drugs amp regimens required for HIV associated TB
- Rifapentine ndash food interactions
- Potential interactions bw fluroquinolones and antiretrovirals
- PXR regulates drug-metabolizing enzymes
- Rifampicin is a potent activator of PXR
- Drug-Drug Interactions
- Combined toxicities
- Role of adjunctive immunotherapy
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
- Supplementing effector cytokines to assist with antimicrobial activity
- Preventing HIV associated TB
- Isoniazid preventive therapy
- Slide Number 25
- LTBI with MDRXDR TB
- Slide Number 27
- Treatment of LTBI
- Slide Number 29
- Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
- Conclusion
- Acknowledgements
-
Conclusion
bull HIV associated TB accounts for the vast majority of TB in sub-Saharan Africa
bull Need new safe short effective regimens for HIV associated TB including MXDR TB
bull Use of adjunctive immunotherapy should be evaluated
bull Need new safe short effective regimens for treating LTBI particularly for DR TB
bull Therapeutic TB vaccines required
Acknowledgements
bull Helen McIlleronbull Ann Ginsburg
- Issues in TB Drug DevelopmentTBHIV
- Presentation outline
- SA has one of the worst TB epidemics in the world
- Integrated TB and HIV treatment saves lives
- Projected use of PI-based ART
- Slide Number 6
- Effect of IPT and ART on TB incidence and mortality
- Effect of IPT and ART on TB incidence and mortality
- Reduction in TB incidence with 36 vs 6 months IPT
- Reduction in TB incidence with 36 vs 6 months IPT
- New drugs amp regimens required for HIV associated TB
- Rifapentine ndash food interactions
- Potential interactions bw fluroquinolones and antiretrovirals
- PXR regulates drug-metabolizing enzymes
- Rifampicin is a potent activator of PXR
- Drug-Drug Interactions
- Combined toxicities
- Role of adjunctive immunotherapy
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
- Supplementing effector cytokines to assist with antimicrobial activity
- Preventing HIV associated TB
- Isoniazid preventive therapy
- Slide Number 25
- LTBI with MDRXDR TB
- Slide Number 27
- Treatment of LTBI
- Slide Number 29
- Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
- Conclusion
- Acknowledgements
-
Acknowledgements
bull Helen McIlleronbull Ann Ginsburg
- Issues in TB Drug DevelopmentTBHIV
- Presentation outline
- SA has one of the worst TB epidemics in the world
- Integrated TB and HIV treatment saves lives
- Projected use of PI-based ART
- Slide Number 6
- Effect of IPT and ART on TB incidence and mortality
- Effect of IPT and ART on TB incidence and mortality
- Reduction in TB incidence with 36 vs 6 months IPT
- Reduction in TB incidence with 36 vs 6 months IPT
- New drugs amp regimens required for HIV associated TB
- Rifapentine ndash food interactions
- Potential interactions bw fluroquinolones and antiretrovirals
- PXR regulates drug-metabolizing enzymes
- Rifampicin is a potent activator of PXR
- Drug-Drug Interactions
- Combined toxicities
- Role of adjunctive immunotherapy
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Immunotherapy that Enhance protective immunity andor down-regulate Th2 activity
- Restoring effectiveness of drugs by disrupting bacteriostatic pathwaysfibrosis
- Supplementing effector cytokines to assist with antimicrobial activity
- Preventing HIV associated TB
- Isoniazid preventive therapy
- Slide Number 25
- LTBI with MDRXDR TB
- Slide Number 27
- Treatment of LTBI
- Slide Number 29
- Therapeutic TB vaccines (RUTI) Histology done 21 weeks after Minipigs infected transthoracicaly (L)
- Conclusion
- Acknowledgements
-