Richard E. Chaisson, MD Center for Tuberculosis Research Johns Hopkins University

Richard E. Chaisson, MD

Center for Tuberculosis Research

Johns Hopkins University

TB/HIV Research Priorities and Recent Developments

Examples of Research Needed

• Basic –immunology, molecular biology, genomics, drug discovery

• Translational – pathogenesis • Clinical – observational, trials, outcomes• Public Health – intervention paradigms• Operational – functional strategies • Health Services – health system structure• Cost-effectiveness – impact on DALYs• Behavioral – health seeking behavior,

delays, clinician behavior

So many questions, so little time…

• Epidemiology of TB/HIV

• Diagnosis of latent and active TB

• TB/HIV clinical issues

• Treatment of TB in setting of HIV– ART, drug interactions and MDR– IRIS– New drugs

• Preventive therapy

• Public health interventions

So many questions, so little time…

• Epidemiology of TB/HIV• Diagnosis of latent and active TB• TB/HIV clinical issues• Treatment of TB in setting of HIV

– ART, drug interactions and MDR– IRIS– New drugs

• Preventive therapy• Public health interventions

Community TB Prevalence in Masipumelela, South Africa

Randomly Selected Community Sample

0

1

2

3

4

5

6

Prevalent Smear + Smear -/Cx+ Total

Per

cent

wit

h T

B

HIV+HIV-

Bekker et al., CROI 2006

So many questions, so little time…

• Epidemiology of TB/HIV

• Diagnosis of latent and active TB

• TB/HIV clinical issues

• Treatment of TB in setting of HIV– ART, drug interactions and MDR– IRIS– New drugs

• Preventive therapy

• Public health interventions

Current Approaches to Diagnosing TB in Resource Poor Settings

• Reliance on antiquated tools with poor sensitivity

Diagnosis of Latent and Active TBOpportunities for Research

• Latent TB– Interferon-gamma based assays– Proteomic-based antigen or antibody detection– Lateral flow and other platforms

• Active TB– MGIT based diagnostics– Novel culture systems– Antigen detection in sputum– Automated nucleic acid amplification

Clinical Markers for Confirming Smear Negative TB in HIV+ Patients in South Africa

• Follow up study in KZN• HIV+ and HIV- patients

with suspected SNTB• Response to therapy

monitored• Response to therapy at

week 8 = 96% for TB patients

0

10

20

30

40

50

60

70

80

90

100

Weight Haemoglobin C-ReactiveProtein

KarnofskyPerformance

Score

SymptomScore Ratio

Per

cen

tag

e o

f su

bje

cts

Week 2 Week 4 Week 8

D Wilson et al., Int J TB Lung Dis, 2006

D Wilson et al., WAC Toronto, Abstract MOPE0145

Cape Town Study, HIV+

Time to Positive Culture by MODS or L-J in 1639 Respiratory Specimens from TB

Suspects in Brazil and Honduras

0

10

20

30

40

50

60

70

80

90

100

0 5 10 15 20 25 30 35 40 45 50 55

Days to M. tuberculosis grow th

% p

ositi

ve fo

r gr

owth

LJ, smear negative

MODS, smear negative

LJ, smear positive

MODS, smear positive

Arias, Dorman et al., 2006

MODS – Sm+ LJ – Sm+

So many questions, so little time…

• Epidemiology of TB/HIV• Diagnosis of latent and active TB• TB/HIV clinical issues• Treatment of TB in setting of HIV

– ART, drug interactions and MDR– IRIS– New drugs

• Preventive therapy• Public health interventions

Impact of an Opt-Out vs. Opt-In Strategy for HIV Testing of TB Patients in the Eastern Cape, South Africa:

A Cluster Randomized Trial

Outcome Opt-Out Clinics Control

(Opt-In)

P-value*

# Range (%) # Range (%)

TB Patients Pre-test counseled

73 3-66 (23%) 31 1-6 (9%) 0.03**

TB Patients HIV tested 71 1-18 (22%) 26 0-6 (8%) 0.03

% counseled that tested 97% 79% 0.12

HIV test positive 31 0-10 (36%) 11 0-3 (43%) 0.75

Prescribed cotrimoxazole 6 0 - 2 (29%) 4 0-2 (33%) 0.89

Referred to ARV clinic 7 0 - 2 (4%) 2 0-1 (27%) 0.33

Pope et al., WAC Toronto, Abstract #THKC205

So many questions, so little time…

• Epidemiology of TB/HIV• Diagnosis of latent and active TB• TB/HIV clinical issues• Treatment of TB in setting of HIV

– ART, drug interactions and MDR– IRIS– New drugs

• Preventive therapy• Public health interventions

ART, Drug Interactions and MDR TB

• TB in patients on ART (Lawn et al., WAC Toronto, #MOPE 0175)

– 944 patients initiating ART in Western Cape– 25% prevalent TB, 10% with new TB– TB incidence after ART 10.4 cases per 100 PY

• MDR TB (Vargas et al., WAC Toronto, Abstract #WEPE0166)

– 209 HIV+/TB patients in Lima– 34% MDR, 10% INH-resistant, median CD4 = 44

• XDR TB (Gandhi et al., WAC Toronto,#THLB0210)

– Epidemic MDR and XDR TB in KZN, South Africa– All XDR TB patients HIV+, 51% with no prior treatment

DTH Responses Measured by Elispot in Patients with and without IRISDTH Responses Measured by Elispot in Patients with and without IRIS

22 HIV-TB co-infected patients prospectively followed after anti-mycobacterial (TBK) then ARV (M0) therapy initiation

IRS+ n=9 (41%) IRS- n=13

p =0.006

NS

T BK M 0 M1 M 3 M60

500

1000

1500

2000

2500

3000

3500

4000

SF

C/1

06 PB

MC

T BK M 0 T IRS M 3 M 60

500

1000

1500

2000

2500

3000

3500

4000 PPD CMV

SF

C/1

06 PB

MC

Bourgarit et al., AIDS. 2006;20:F1-7, CROI 2006

TBTC Study 27: Moxifloxacin vs. Ethambutol as 4th Drug in Initial Treatment of Smear+ TB

Proportion of Patients with Negative Culture

01020304050607080

2 4 6 8

Weeks of treatment

Spu

tum

cul

ture

co

nver

sion Moxifloxacin

Ethambutol

P=0.02 P=0.003

Median Time to Culture Conversion: Moxi 43 d vs. EMB 56 d (p=0.01)

Burman et al., AJRCCM 2006;174:331-8

TBTC Study 27Sputum culture conversion

among key sub-groups

CavitationNo cavitation

Age <31 yearsAge >31 years

AfricanNorth American

Culture conversion

66% (137/206)84% ( 60/71)

66% ( 89/134)76% (108/143)

63% (110/175)85% ( 87/102)

Adjusted P

0.03

0.003

<0.0001

Burman et al., AJRCCM 2006;174:331-8

CFU counts after 2 months treatment

0

1

2

3

4

5

6

7

8

Pre-Rx RMZ RMZPa PaMZ RPaZ RMPa

Regimen

Lo

g(1

0) C

FU

co

un

t

Lung

Spleen

R, rifampin; M, moxifloxacin; Z, pyrazinamide; Pa, PA-824.

Moxifloxacin and PA-824 in a Murine TB Model

Nuermberger et al., Antimicrob Agents Chemother 2006;50:2621

So many questions, so little time…

• Epidemiology of TB/HIV• Diagnosis of latent and active TB• TB/HIV clinical issues• Treatment of TB in setting of HIV

– ART, drug interactions and MDR– IRIS– New drugs

• Preventive therapy• Public health interventions

TB Incidence in Brazilian HIVPatients by Treatment Category

Treatment category

Person-Years

TB Cases

Incidence Rate(per 100 PYs)

Naïve 3,865 157 4.06 (3.45-4.75

HAART only 11,629 229 1.97 (1.72-2.24)

INH only 395 5 1.27 (0.41-2.95)

HAART and INH

1,253 13 1.04 (0.55-1.78)

Total 17,142 404 2.36 (2.13-2.60)

Golub et al., WAC Toronto, Abstract MOPE0395

Novel TB Preventive Regimens in HIV-Infected Adults in Soweto: PHRU/JHU Trial

• Open label, randomized trial• HIV+/PPD+ adults not on HAART at enrollment• Active TB excluded (23% screen failures TB+)• Regimens

– Rifapentine 900 mg/INH 900 weekly for 12 weeks

– Rifampin 600 mg/INH 600 mg twice weekly for 12 weeks

– INH 300 mg daily continuously

– INH 300 mg daily for 6 months

• Endpoint – TB-free survival

Probability of TB After Enrollment (All Treatment Groups)

So many questions, so little time…

• Epidemiology of TB/HIV• Diagnosis of latent and active TB• TB/HIV clinical issues• Treatment of TB in setting of HIV

– ART, drug interactions and MDR– IRIS– New drugs

• Preventive therapy• Public health interventions

Study/Site Intervention(s) Design (N)

Thibela TB

SA Gold Mines

Mass preventive therapy

Cluster randomized trial

(>40,000)

ZAMSTAR

Zambia/South Africa

Intensive case finding, household

interventions

Community randomized trial

(~2 million)

THRio

Rio de Janeiro

Preventive therapy and ARVs

Phased implementation

trial

(12,000)

C R E A E

Research in TB/HIVResearch in TB/HIV

• The need is enormous

• There are abundant opportunities to contribute

• Interdisciplinary and novel approaches are needed

• New paradigms must be developed• “The greatest obstacle to discovery is

not ignorance - it is the illusion of knowledge.” --Daniel Boorstein

• The need is enormous

• There are abundant opportunities to contribute

• Interdisciplinary and novel approaches are needed

• New paradigms must be developed• “The greatest obstacle to discovery is

not ignorance - it is the illusion of knowledge.” --Daniel Boorstein