Transcript priorities and ongoing research efforts

TB/HIV meeting at 14th conference on retroviruses and opportunistic infections
Sunday, 25 February 2007
HIV treatment for TB patients:
priorities and ongoing research
efforts
Fabio Scano
Stop TB, WHO
outline
• WHEN to start ART
• WHAT to start
• Other areas of research
– TB in patients on ART
– Rifabutin
– New drugs
• Future directions
Initiating first line ART in relationship to starting anti-TB therapy
CD4 Cell Count
ART recommendations
Timing of ART in
relation the start of
TB treatment
CD4  200 cells/mm3
Recommend ART
CD4 between 200-350 cells/mm3
Recommend ART
After 8 weeks
CD4  350 cells/ mm3
Do not initiate ART c
Re-evaluate patient at 8 weeks
and at the end of TB treatment
CD4 not available
Recommend ART
a
d
Between 2-8 weeks b
Between 2-8 weeks
WHO Guidelines, 2006
Validating the optimal time to start
ART: ongoing efforts
Trial
CD4
regimens
timing
CAMELIA
ANRS 1295/NIH
<200
N=570
EFV/D4T/3TC
2 vs. 8 weeks
AA5221
NIH
<200
N=800
EFV/TDF/FTC
2 vs. 8-12 weeks
START
NIH
>50
N=592
EFV/3TC/DDI
Immediate vs. 8
weeks TB
Early arm within the TB
programme
Start date?
EDCTP/TDR
Uganda/Tanzania
N=1800
EFV/3TC/AZT
immediate vs. after
TB treatment
Due to start in March 2007
Haiti (not only TB)
>200 or 350
AZT/3TC/EFV
CD cell count
driven
Recruitment not started
yet
PART Study
Uganda
>350 or < 200
ABC/AZT/3TC
CD4 count driven
Recruitment started in
2005
Started in January 2006
What to start
2006 WHO Guidelines:
First Line ART Regimens and Active TB
Regimen
Recommendation
Monitoring
EFV/2NRTI
Preferred
Pregnancy
NVP/2NRTI
Alternate
ALT*
Triple NRTI1
Alternate
HSR2 with abacavir
*Patient education, bi-weekly visits,
ALT/AST at 0,2,4,8 and 12 weeks
1 ZDV/3TC/ABC
or ZDV/3TC/TDF
2 Hypersensitivity reaction
Rifampin Interactions: Is dose
adjustment required?
• EFV and NVP are reduced 20-40% with
rifampin1,2,3,4
• Small PK studies support dose increase
of EFV (800 mg) and NVP(300 mg bid) 5,6
• Large interpatient variability due to
genetic determinants of metabolism7
• Clinical outcome studies to date do not
support dose adjustment of EFV or NVP
5 Lopez-Cortes,
1Ribera,
2Lopez-Cortes,
JAIDS, 2001;
Clinical PK, 2002; 3Manosuthi, AIDS,
2005 ; 4Manosuthi, CID, 2006
Clinical PK, 2002;
JAIDS, 2006; 7Haas, AIDS,
2004; Friedland J, Antimicrob. Chemotherapy
2006.
6Ramachandran,
Efavirenz vs. Nevirapine
Trial
CD4
South Africa
(Khayelitsha)
regimens
Timing
comments
EFV vs NVP
A 6 arm trial
Virological outcome
Not powered to
determine safety
India
(National AIDS control
org)
< 250
EFV or
NVP/ddI/3TC
8 weeks
Started in March 2006
HIV/NAT
Multicentre study
n/a
NVP 400 mg vs.
600 mg
2-6 weeks
A 48 week, randomized,
open-label, 2 arm study to
compare the efficacy, safety
and tolerability . Started in
2005
Mozambique
(Epicentre/MSF/MoH)
ANRS
<200
and
<350
EFV or NVP
4 weeks
Viral load at 12 mo
and safety.
To start in June 2007.
Burkina Faso
< 200
EFV or NVP
/3TC/AZT
Malawi
Two sites
N=3820
RIF vs RFB
with NVP/3TC/d4T
2 weeks vs 8
weeks
A four arm, double
blinded, randomized
Potential toxicity between ART
and TB medications
Overlapping toxicity
Hepatitis
Antiretroviral agent
NVP, EFV
Anti-TB agent
RIF, PZA. INH, Eto/Pto,
PAS, E, FQ
Haematological
AZT
linezolid
CNS
EFV
CS, H, FQ, Eto/Pto
GI
All
Rif, Pza, Eto/Pto, PAS, Cfz,
Lzd
Neuropathy
d4T
CS, INH, E
TB in patients receiving ART
New Pulmonary TB
NEW TB
ART THERAPY
2
0
6
48
96
MONTH ON ARV
Undiagnosed TB
Activation of latent TB
Treatment failure if:
CD4 guided
Transmitted TB
IRIS
Other conditions
Second Line ART
•Drug interactions between rifampin and
protease inhibitors
•Drug toxicity/tolerability
•Drug Cost
RMP vs. RFB with PI based
regimens
Drug
Unit cost
TB Treatment Rifampicin +
regimen cost boosted
ritonavir
*Rifabutin
0.85 USD
61-122 USD
Rifampicin
0.049USD
8.82 USD
Ritonavir
price
0.374 USD
210.78 USD
Rifabutin +
standard
dose of RTN
61-122 USD
*Toxicity: marrow suppression, contraindicated WBC <1000, Plts <50k , also
arthralgias, uveitis
Discovery - 17
Cell Wall Inhibitors
NIAID, Colorado State University
Nitroimidazole Analogs
Novartis Institute for Tropical Diseases,
NIAID, TB Alliance
Preclinical - 4
Clinical Testing - 5
Diamine SQ-109
Sequella Inc.
Diarylquinoline R207910
Johnson & Johnson
Dihydrolipoamide Acyltransferase
Inhibitors
NIAID, Cornell University
Novel Antibiotic Class
GlaxoSmithKline, TB Alliance
Nitroimidazole PA-824
Chiron Corporation, TB Alliance
Gatifloxacin
Dipiperidines
Sequella Inc.
Picolinamide Imidazoles
NIAID, TAACF)
Synthase Inhibitor FAS20013
FASgen Inc.
Moxifloxacin
InhA Inhibitors
GlaxoSmithKline, TB Alliance
Pleuromutilins
GlaxoSmithKline, TB Alliance
Translocase I Inhibitors
Sequella Inc., Sankyo
Proprietary Compound
Otsuka
Isocitrate Lyase Inhibitors (ICL)
GlaxoSmithKline, TB Alliance
Pyrroles
(TB Alliance, Private Sector Partner)
Macrolides
TB Alliance, University of Illinois at Chicago
Quinolones
Methyltransferase inhibitors
Anacor Pharmaceuticals
Proprietary Compounds
AstraZeneca
Natural Products Exploration
Thiolactomycin Analogs
NIAID, NIH
NIAID, TAACF, California State University,
University of Auckland
Nitrofuranylamides
NIAID, University of Tennessee
KRICT/ Yonsei University, NIAID,
TAACF, TB Alliance
OFLOTUB – TDR, Tuberculosis Research Centre,
NIAID, TBRU
Bayer Pharmaceuticals, CDC TBTC,
Johns Hopkins University, NIAID, TBRU
Pyrrole LL-3858
Lupin Limited
Future directions
More research to optimize: Time of initiation, First line ART
(safety and tolerability)
Urgent research for new ART friendly-drugs, rifabutin,
implications for M-XDR/TB.
Questions:
1 How ANRS, NIH, EDCTP can ensure that HIV trials are well
designed to reflect TB issues
2. How to ensure that these research priorities are well
prioritised within the funding streams.