HIV treatment for TB patients:priorities and ongoing research

efforts

Fabio Scano

Stop TB, WHO

TB/HIV meeting at 14th conference on retroviruses and opportunistic infectionsSunday, 25 February 2007

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 recommendationsTiming of ART in

relation the start of TB treatment

CD4 200 cells/mm3 Recommend ART a Between 2-8 weeks b

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 d 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 Started in January 2006

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

What to start

2006 WHO Guidelines:

First Line ART Regimens and Active TB

1 ZDV/3TC/ABC or ZDV/3TC/TDF 2 Hypersensitivity reaction

*Patient education, bi-weekly visits, ALT/AST at 0,2,4,8 and 12 weeks

Regimen Recommendation Monitoring

EFV/2NRTI Preferred Pregnancy

NVP/2NRTI Alternate ALT*

Triple NRTI1 Alternate HSR2 with abacavir

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

1Ribera, JAIDS, 2001; 2Lopez-Cortes, Clinical PK, 2002; 3Manosuthi, AIDS, 2005 ; 4Manosuthi, CID, 2006

5 Lopez-Cortes, Clinical PK, 2002; 6Ramachandran, JAIDS, 2006; 7Haas, AIDS, 2004; Friedland J, Antimicrob. Chemotherapy 2006.

Efavirenz vs. Nevirapine Trial CD4 regimens Timing comments

South Africa (Khayelitsha)

EFV vs NVP A 6 arm trial

Not powered to determine safety

Virological outcome

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 Antiretroviral agent Anti-TB agent

Hepatitis NVP, EFV 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

ART THERAPY

0

MONTH ON ARV

964862

TB in patients receiving ART

NEW TB

Undiagnosed TB

Activation of latent TB

IRISTransmitted TB

New Pulmonary TB

Treatment failure if:

CD4 guided

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 regimen cost

Rifampicin + boosted ritonavir

Rifabutin + standard dose of RTN

*Rifabutin 0.85 USD 61-122 USD

Rifampicin 0.049USD 8.82 USD

Ritonavir price

0.374 USD

210.78 USD 61-122 USD

*Toxicity: marrow suppression, contraindicated WBC <1000, Plts <50k , also arthralgias, uveitis

Discovery - 17 Preclinical - 4 Clinical Testing - 5

Dihydrolipoamide Acyltransferase InhibitorsNIAID, Cornell University

DipiperidinesSequella Inc.

InhA InhibitorsGlaxoSmithKline, TB Alliance

Isocitrate Lyase Inhibitors (ICL) GlaxoSmithKline, TB Alliance

MacrolidesTB Alliance, University of Illinois at Chicago

Methyltransferase inhibitorsAnacor Pharmaceuticals

Translocase I InhibitorsSequella Inc., Sankyo

Synthase Inhibitor FAS20013FASgen Inc.

Moxifloxacin Bayer Pharmaceuticals, CDC TBTC, Johns Hopkins University, NIAID, TBRU

Diarylquinoline R207910Johnson & Johnson

Proprietary Compound Otsuka

Natural Products Exploration NIAID, TAACF, California State University, University of Auckland

Nitroimidazole PA-824 Chiron Corporation, TB Alliance

Diamine SQ-109Sequella Inc.

GatifloxacinOFLOTUB – TDR, Tuberculosis Research Centre, NIAID, TBRU

Cell Wall InhibitorsNIAID, Colorado State University

Novel Antibiotic ClassGlaxoSmithKline, TB Alliance

Picolinamide ImidazolesNIAID, TAACF)

PleuromutilinsGlaxoSmithKline, TB Alliance

Pyrroles(TB Alliance, Private Sector Partner)

QuinolonesKRICT/ Yonsei University, NIAID, TAACF, TB Alliance

Proprietary CompoundsAstraZeneca

Thiolactomycin AnalogsNIAID, NIH

Nitroimidazole Analogs Novartis Institute for Tropical Diseases, NIAID, TB Alliance

Nitrofuranylamides NIAID, University of Tennessee

Pyrrole LL-3858Lupin 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.