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TB and HIV:

An introduction for journalists

E Jane Carter, MD President, International Union Against TB and Lung Disease

Associate Professor, Warren Alpert School of Medicine at Brown University

Providence, Rhode Island USA

Presentation Outline

Unique Symbiosis of the two epidemics

Diagnosis

HIV in TB patients TB in HIV patients

Treatment

Timing of therapy for each Drug Interactions and Compatibilities IRIS

Programmatic support

What individual Care providers can do to support TB Control

TB

Leading cause of death from a single agent

Leading cause of death in women of child bearing years

Leading cause of death in PLWAs 5000 individuals die each day One person is infected every second

3600 will be infected during this lecture

Dynamics of TB and HIV in Kenya

190 30 TB 170 25 HIV 150 HIV-Nairobi 20 130 15 110 10 90 5 70
190
30
TB
170
25
HIV
150
HIV-Nairobi
20
130
15
110
10
90
5
70
50
0
1975
1980
1985
1990
1995
2000
TB incidence/100,000
HIV pevalence adults (%)

Critical Terminology

Exposure

Infection

Disease

Contagion

Everything at the

bottom of the list

requires those steps above it to occur; each

step does not have to

occur, however.

What do we know about TB/HIV?

No clear data that Patients with HIV have an increased chance of infection if exposed

Patients with HIV have a higher risk of developing TB if TB infected

40% with recent exposure

Daley NEJM 1992;326:231-5

10% annually with LTBI

Selwyn NEJM 1989;320:545-50

What do we know about TB/HIV?

Patients with advanced HIV have an accelerated course from infection to disease

Time line infection to death as little as 12 weeks

Daley NEJM 1992;326:231-5

After initiating HAART for HIV, patients still have a higher rate of developing TB than an HIV negative patient

25% reduction in risk for every 100 CD4 increase

Lawn AIDS 2006;20:1605-12

WHO recommendations

Screen all TB patients for HIV Screen all HIV patients for TB

Screen for HIV in TB patients

Theoretically should be easy

HIV tests are easy to use HIV testing has high sensitivity and specificity

The window period for “false negative” tests during seroconversion is short

One time only unless new HIV risk factors identified

Needs testing early in care ART eligible

Rates of HIV testing in TB Patients

Country

HIV testing rates

China

34%

Kenya

94%

Pakistan

4%

India

56%

Why are reported testing rates so low?

Availability of test kits Availability of Counselors

Diagnostic Testing and Counseling Voluntary Counseling and Testing

Stigma Reticence of health Care Providers

Diagnosis of TB in HIV patients

More difficult for a variety of reasons Present state of the art for Testing for TB is poor

Latent TB Infection

Tuberculin skin testing or Interferon Gamma Release Assay

Active TB

Gold standard is based on identification of organism. Smear is insensitive Culture is often unavailable

Even when culture is available, 20% of TB cases are culture negative and based on clinical presentation and the response to therapy

TB Diagnosis

TB Diagnosis
TB Diagnosis

Diagnosis of TB in HIV patients

Wide range of presentations for TB- The great masquerader

Extrapulmonary disease more common in HIV patients

Smear negative disease is more common in HIV patients

Culture positive TB with a normal chest radiograph clearly occurs

The window of opportunity to diagnose TB is shortened

Challenge is to think TB on every interaction with the HIV patient

Challenges in TB Diagnosis in HIV

Tanzania

Screening for a Vaccine trial HIV + patients CD4 <200, n=93 14 had clinical TB 4 had subclinical TB

AFB+/culture + but no symptoms and normal CXR

6 had no symptoms

Culture +

Mtei L. Clin Infect Dis 2005;40:1500-7

Algorithm for TB Screening

in HIV+ Persons

1,748 HIV+ persons in Cambodia, Thailand, and Vietnam

TB diagnosed in 267 (15%)

Presence of cough for > 2-3 weeks during the preceding 4 weeks:

22-33% sensitive

82-88% specific

Presence of at least one (cough any duration, fever any duration, night sweats for > 3 weeks in preceding 4 wks)

93% sensitive

36% specific

– – 97% negative predictive value

Cain NEJM 2010;362(8)

Cain KP. N Engl J Med 2010;362:707-16.

Screen for TB and HIV?

TB patients

All TB patients should be screened for HIV

Theoretically not difficult

HIV patients

All HIV patients should be screened for TB

More difficult

Rapid HIV testing or standard Elisa/western blot

TB infection versus TB disease

Sensitivity and specificity of testing is high

Diagnostic testing more challenging

One time only unless new HIV risk factors identified Needs testing early in care ART eligible

Repeatedly performed

Risk continues for both TB

infection/reinfection and

disease as long as patient lives in high incidence region

Treatment Issues

Challenges of Concomitant TB/HIV

Treatment

Challenges of Concomitant TB/HIV Treatment

Is it necessary to Treat Concomitantly?

Retrospective Studies Madrid* Meta-analysis of 6934 patients

63% increase in survival amongst patients initiating ART during TB therapy

Thailand** study of 1003

20 X greater mortality risk in patients receiving only TB compared to those receiving ART/TB

*Velasco et. al. JAIDS 2009;50:148-52. **Manosuthi et. al. JAIDS 2006;43:42-6.

Is it necessary to Treat Concomitantly?

Prospective, open label, randomized Control trial, South Africa

Three arms

start ARV (EFV, dDI, 3TC) within 4 weeks of starting TB therapy

start ARV within 4 weeks of continuation phase of TB therapy

start ARV within 4 weeks of completing TB therapy

Arm 3 halted after enrollment complete

N Engl J Med 2010;362:697-706.

Reduction in mortality in combined treatment versus sequential therapy

5.4 deaths/100 person years group 1 and 2 12.1 deaths/100 person years group 3

hazard ratio in the combined integrated-therapy groups, 0.44 95% confidence interval, 0.25 to 0.79; P = 0.003

Mortality lower in all cd4 stratifications Adverse events in groups were not different

Need to start but When?

Retrospective study, Spain

313 patients

Lower mortality (9 vs 20%) in patients started on ART within 2 months of TB therapy*

Retrospective study,

Patients with CD 4 <100

Initiate ART at 2 weeks after starting TB rather than 8 weeks reduced mortality Iran had no significant difference in adverse effects including IRIS

WHO current guidelines recommend starting ARV therapy between 2 and 8 weeks in patients with CD

4

of

<200 cells/mm 3 and during continuation phase in those with CD4 counts 200-350

*Velasco et al JAIDS 2009;50:148-152. **Tabarsi et al J Int AIDS Soc 2009;12:14

Drug Pairing

TB Treatment Regimen: HRZE 2 HR 4 Rifampin Interaction:

Key site of interactions involving ARV and the rifamycins is the hepatic cytochrome P450-3A4 (CYP3A4) and 2B6 (CYP2B6) isoforms

Induction of CYP3A4 and 2B6 by the rifamycins significantly reduces levels and exposure to the PIs and NNRTIs

Rifampin >>> Rifabutin > Rifapentine

Rifapentine use has been associated with R resistant TB relapse

Intermittent dosing with Rifabutin may lead to R Resistant TB relapse

What can be used with Rifampin?

(What is not effected by the P450

cytochrome system)

NRTIs- all Ok NNRTIs

Efavirenz is best and least effected

Conflicting data about Nevirapine so would NOT be first choice

PIs

All go through the Cytochrome P450 system

Only boosted PIs are possible but risk of hepatitis and/or intolerance is high

The Dreaded Complication

Immune Reconstitution

Inflammatory Syndrome

Effect of HAART on TB risk

Overall, immune reconstitution due to HAART decreases, not

increases, TB risk

Effect of HAART on TB risk • Overall, immune reconstitution due to HAART decreases, not increases,

Jones JL. Int J Tuberc Lung Dis 2000;4:1026AASD Badri M. Lancet 2002;359:2059-64

Schematic representation of the different forms of TB-associated IRIS and ART- associated TB

Schematic representation of the different forms of TB-associated IRIS and ART- associated TB • Previously undiagnosed

Previously undiagnosed prevalent TB Newly-acquired TB Progression of sub-clinical TB present before ART (reactivation) A sub-set have IRIS

Meintjes G. Lancet Infect Dis 2008. Lawn SD. AJRCCM 2008.

Manabe Y. J Infect Dis 2009.

TB Adenitis/IRIS

TB Adenitis/IRIS

WHO Programmatic Issues for TB/HIV The Three I’s

Intensified Case Finding Isoniazid Preventive Therapy

Infection Control

Intensified Case Finding

Physician

Screen every patient with TB for HIV

Screen every HIV patient for TB

At every encounter

Program

Promotion of Universal HIV testing

Removal of system barriers to access care

and early screening for TB

HAART and INH

TB Prevention in HIV

Rio de Janeiro, Brazil

11,026 HIV + persons receiving care at 29 public clinics, Sept

2003-Sept 2005

Intervention

TB per 100 p-y

No HAART/no INH

4.01

HAART

1.90

INH

1.27

HAART and INH

0.80

After adjusting for age, previous TB, and baseline CD4, 76% in TB risk if received HAART and INH compared to no HAART/no INH

Golub J. AIDS 2007;21:1441-8.

HAART and INH

TB Prevention in HIV

Urban and rural South Africa

 

2,778 HIV + persons receiving care at 2 hospital-based clinics,

June 2003-Dec 2007

 

Intervention

TB per 100 p-y

 
 

No HAART/no INH

 

7.1

HAART

4.6

INH

5.2

HAART and INH

1.1

After adjusting for age, sex, clinic location, and baseline CD4:

64% in TB risk if received HAART; 89% in TB if received ART after INH

Golub J. AIDS 2009;23:631-6.

Algorithm for TB Screening

in HIV+ Persons

1,748 HIV+ persons in Cambodia, Thailand, and Vietnam

TB diagnosed in 267 (15%)

Presence of cough for > 2-3 weeks during the preceding 4 weeks:

22-33% sensitive

82-88% specific

Presence of at least one (cough any duration, fever any duration, night sweats for > 3 weeks in preceding 4 wks)

93% sensitive

36% specific

– – 97% negative predictive value

Cain NEJM 2010;362(8)

Cain KP. N Engl J Med 2010;362:707-16.

Infection Control

Administrative Controls

Early Detection Effective Therapy for TB

Ensure completion of therapy

Environmental Controls

Ventilation Ultraviolet light

Personal Respiratory Devices

Least effective and least studied

Conclusions

To treat TB and HIV adequately, the first step is improved diagnosis.

Concomitant therapy reduces mortality timing of treatment is the challenge ( during TB induction phase is clear)

IRIS, through a risk, is not a reason to not start

ART.

Intensified case finding is necessary to reduce community burden and transmission. Early

diagnosis and initiation of therapy is the best infection control.

The International Union Against TB and Lung Disease Health Solutions for the Poor www.theunion.org Questions?

The International Union Against TB and Lung Disease

Health Solutions for the Poor

www.theunion.org

Questions?