TB/HIV CO-INFECTION

Jantjie Taljaard

Centre for Infectious Diseases (CID)

Department of Medicine - University of Stellenbosch

April 2010

Overview

• Epidemiology

• Pathogeneses & Immunology

• Clinical picture

• Diagnosis

• Expanded Clinical case definitions

• TB Prophylaxis

The global perspective on TBThe global perspective on TB

• 1/3 of the world’s population has TB infection

• 9 million people globally develops TB disease

• Globally, 2 million TB-related deaths a year

– TB is the leading killer of HIV-infected people

• The number of new TB cases is falling or

stabilized in five of six continents

• 1/3 of the world’s population has TB infection

• 9 million people globally develops TB disease

• Globally, 2 million TB-related deaths a year

– TB is the leading killer of HIV-infected people

• The number of new TB cases is falling or

stabilized in five of six continents

African perspective on TB/HIV co-

infection

• Africa is the one continent where TB rates are rising• enough to increase global rates

• HIV infection is now the most important predictor of TB incidence across the Africancontinent

South

Africa

19%

South

Africa

19%

“Basic” TB immunology

• Inhalation of mycobacteria

• Alveolar macrophages produce cytokines

• Macrophage activation and enhanced

killing of ingested organisms

• Activation of T-cells → clonal expansion

• T-cells also produce IFN-γ• Results in granuloma formation →

containment and destruction of infection

• The CD4+T-cell subset is central for granuloma

formation and prevention of dissemination

• BUT….this immunological response is unable

to destroy all viable organisms

• The surviving, but dormant organisms causes

latent infection, which is diagnosed by a

positive tuberculin test

(active immunosurveillance maintains the latency of

dormant foci)

“Basic” TB immunology

How does HIV impact on TB?

• HIV → CD4+T-cell depletion → defective

immunologic response to M.TB.

• HIV-infected individuals with:

– latent TB are at high risk for reactivation

– recently acquired TB are at high risk for progressive

primary TB

• TB in immunocompromised individuals often

pursues an unusual course

Effect of TB disease on HIV

• TB activates CD4+ cells and macrophages

harboring latent HIV �increases the ability of

HIV to replicate � Increased viral load

– TB accelerates the progression of HIV to AIDS

• TB is the leading killer of HIV-infected persons

– The life expectancy of a HIV-infected person with low CD4 count and TB disease is measured in weeks if treatment is not available

Min-Max25%-75%Median value

TB diagnosis date

Med

ian

CD

4 T

-lym

phoc

yte

(Cel

ls/u

l)

0

80

160

240

320

400

480

560

CD4BEFORE CD4AT CD4AFTR

p = 0.03p< 0.01

p = 0.35

CD4+ counts

(p=45)

Int J Tuberc Lung Dis 2001; 5: 225Int J Tuberc Lung Dis 2001; 5: 225--232.232.

Alarmingly, fewer than half of TB

cases in HIV-infected patients are

diagnosed before death

1. Mohar A, Romo J, Salido F et al. (1992). AIDS, 6, 467–473.

2. Lucas SB, Hounnow A, Peacock C et al. (1993). AIDS, 7, 1569–1579.

3. Domousa K, N’Dhatz M, Coulibaly G et al. (1995). Med Trop (Mars), 55,

252–254.

4. Rana FS, Hawken MP, Mwachari C et al. (2000). J Acquir Immune Defic

Syndr, 24, 23–29.

Factors underlying our failure to rapidly

diagnose and effectively treat TB

• Co-infected patients progress more rapidly from

infection to active disease

– Reduced time available for diagnosis and treatment

• Stigmatization of persons living with HIV/TB

– Reluctance to seek medical assistance

• Limited health-care provision in resource-poor

countries

– Poor access to treatment

• Lack of a sensitive, specific, rapid point-of-care

diagnostic test

Pathogeneses

• Tuberculosis is transmitted via small droplet nucluei containing Mycobacterium tuberculosis bacilli.

• Risk for infection occurs when these droplets becomes aerolised by– Coughing, sneezing, talking, singing or – By aerolising procedures which induce coughing

or access to the respiratory tract such as sputum induction, bronchoscopy, ventilation, physiotherapy, open surgery (including post mortem dissection) etc.

RISKS FOR EXPOSURE

1. Number of infectious cases

2. Duration of infectiousness

3. Number/nature of case contact interactions

per unit time

RISK FOR INFECTION(largely exogenous in nature)

1. Number of infected droplet nuclei per unit of air

2. Duration of exposure to this particle density

RISKS FOR TB DISEASE(largely endogenous = integrity of cellular

immunity)

1. Time since infection

– Lifetime risk = 10% (immunocompetent)

– Highest in first 2 years

– Recent infection 10x more likely to produce

disease

2. Susceptibility of the individual– HIV infection - increases both risk of infection

and reactivation of TB • Annual risk 10%

• Early “OI” - 3 years

• Increased frequency with progression of HIV disease

– Environmental factors• Alcohol and smoking….

• Malnutrition – lactovegetarians, Vit D deficiency

• Stress etc….?

– Other medical conditions• Sillicosis, DM, Malignancies, Renal failure,, Steroid

therapy, Immunosuppressive therapies, Pregnancy

TB DISEASE

Disease develops as a consequence of:

1. Progression of primary infection

2. Post primary disease

a. Endogenous reactivation

b. Exogenous re-infection

Pathogenesis TB Infection and Disease

EXPOSURE TO TB

LATENT TB INFECTION

(90%)

ACTIVE TB DISEASE

(Progressive primary

disease)

(10%)

POST PRIMARY TB DISEASE

(10% lifetime risk)*

LATENT TB

- Never develop disease

RE-INFECTIONREACTIVATION

PRIMARY INFECTION

(10-30%)

NON INFECTION

(70-90%)

* 10% annual risk if HIV co-infected

Clinical PictureClinical Picture

Clinical picture of HIV-associated TB (Influenced by degree of immunodeficiency)

• Early disease

– clinical features resemble those seen in HIV-negative patients with PTB

– often sputum smear positive

• Progressive disease

– atypical PTB, extrapulmonary TB and disseminated TB become more common

– often sputum smear negative

Management

• CXR

Chest x-ray in TB/HIV

• CXR only helps with diagnosis when:

– Negative sputum smears in a patient who continues to cough despite a full course of broad-spectrum antibiotic

• CXR findings often atypical:

– pulmonary infiltrates throughout the lungs rather than cavities in the upper lobes

– abnormalities may be due to other conditions

– former TB patients may have been cured and CXR lesions could incorrectly be read as active TB

Common CXR findings in TB/HIV

• Cavitation

• Focal infiltrates in upper and hilar regions

• Hilar adenopathy

• Pleural or pericardial effusions

• Milliary TB

Pulmonary Tuberculosis

and withwithout

significant immunosuppression

Diagnosis of TBDiagnosis of TB

Diagnosis of TB in HIV

• Protocol for diagnosis of TB follows the same

principles, irrespective of the patient’s HIV

status...BUT

• The diagnosis of TB in HIV+ persons is more

difficult:

– increased frequency of sputum smear negative

disease (pulmonary or extra-pulmonary)

– increased atypical radiology

Sputum microscopy

• Two methods available for direct examination

of sputum:

– Conventional carbol-fuschin staining [Ziehl–

Neelsen (ZN)]

– Auramine stains based on fluorescent microscopy

• The sensitivity of conventional microscopy is

highly variable depending on the setting,

ranging from 20 to 80%

Conventional Sputum Culture

• Gold standard for diagnosis of TB

– Lowenstein-Jensen solid phase culture

• Increases number of cases by up to 50%

• Can detect cases before they become infectious

• Process is slow, thereby reducing its immediate use in clinical practice

Does induction of sputum with nebulised

saline increase diagnostic yield?

• High-income countries– A single specimen of induced sputum is

comparable in diagnostic yield with a BAL specimen from fiberoptic bronchoscopy

– The yield is further increased with repeat specimens

Anderson C, Inhaber N, Menzies RL. (1995). Am J Resp Crit Care Med, 152, 1570–74

Conde MB, Soares LM, Mello CQ et al. (2000). Am J Respir Crit Care Med, 162, 2238–40

• South Africa

– In a study of smear-negative TB in HIV patients in Cape Town

• 72% of cultures from sputum induction in 110 patients were positive for M. tb, including 56% of cases that did not have pulmonary infiltrates on CXR

Wilson D, Nachega J, Morroni C, Chaisson R, Maartens G. (2006). Int J Tuberc Lung Dis, 10, 31–38.

Rapid Mycobacterial Culture

• Automated systems based on fluorescence

such as BACTEC 9000 and MGIT

(Mycobacterial Growth Indicator Tube)

• Microscopic observation drug susceptability

(MODS) assay – characteristic “cording growth

pattern”

• Time to culture positivity:

– MODS - median 7 days (IQR 6–8)

– Automated - 13 days (IQR 10–16)

– Solid-phase culture - 26 days (IQR 21–33)

Rapid Mycobacterial Culture (MODS)

• MODS assay represents a major potential

advance in rapid culture-based diagnosis of

TB, especially in resource-poor countries with

basic laboratory facilities.

• However:

– further studies needed to address the

performance of MODS in smear-negative TB cases

Nucleic acid amplification tests (PCR)

• Many meta-analyses studying the

performance of PCR for diagnosis of smear-

positive and smear-negative TB

– The main use of PCR tests is restricted to

confirming the presence of M. tb in smear positive

sputum samples in a low TB burden setting

Greco S, Girardi E, Navarra A, Saltini C. (2006) Thorax 61, 783–790.

Nucleic acid amplification tests (PCR)

• Current NAA tests exhibit poor sensitivity in

those with smear-negative TBSarmiento OL, Weigle KA, Alexander J, Weber DJ, Miller WC. (2003. J Clin

Microbiol, 41, 3233–3240.

• Furthermore:

– Wide variation in reported performance suggests

that they may also be highly operator dependent

– Such tests are unable to distinguish live from dead

mycobacteria

TST and interferon-gamma release

assays in rapid diagnosis of active TB QuantiFERON-TB gold and ELISPOT assay

• In populations with high rates of TB they

cannot distinguish between LTBI and active

infection

Clinical case definitions for smear

negative TB in HIV infected

patients

Adapted and reproduced with permission of G Maartens.

*CDC case definition: Bilateral interstitial infiltrate, exertional dyspnoea (onset <3

months), hypoxia or desaturation 5% or more on effort.

Smear-negative tuberculosis case definitions PPV (%)

Pulmonary

• Cough for >21 days +

•Pulmonary opacification or nodular infiltrate on CXR + PJP

excluded (using CDC clinical case definition) * +

•No resolution after Rx with broad spectrum antibiotics

who are started on anti-TB Rx after cultures are sent.

92

LymphadenopathyPeripheral

Significant asymmetrical nodes (long axis 3 cm) + fever >38°C on two

occasions OR drenching sweats for 2 weeks

Visceral

Visceral nodes (mediastinal / hilar / abdominal nodes on imaging) + fever

38°C on 2 occasions OR drenching sweats for 2 weeks

94

94–96

SerositisPleural effusion:

Lymphocytic exudate

Pericardial effusion:

Effusion on ultrasound + fever 38°C on two occasions OR drenching

sweats for 2 weeks

Ascites:

Lymphocytic exudate + fever 38°C on two occasions OR drenching

sweats for 2 weeks

85

90

100

Constitutional syndromeWasting (BMI < 18.5) OR documented weight loss >5% body weight

within a month + fever >38°C on two occasions OR drenching sweats for

2 weeks

36

1 Weight gain of 5%

2 Haemoglobin increase of 1g/dl

3 Reduction in CRP

4 Increase in Karnofsky performance score of 20 (or 10 if baseline was ≥ 80)

5 Symptom count ratio > 0.5 (number of symptoms better or resolved at 8 weeks

follow-up/total number of symptoms at baseline

> 1 of these response criteria at week 8 of follow-up =

97.5% confirmed TB

Wilson D, Nachega J, Morroni C, Chaisson R, Maartens G. (2006). Int J Tuberc Lung Dis, 10, 31–38.

Criteria that defines a clinically

relevant response to TB treatment

Treatment of TB DiseaseTreatment of TB Disease

o Use multiple drugs in combination tablets

o Patients must be DOT supported

o Use standardised treatment regimens

o Cure patients the first time round!!

o Give the correct drugs for the correct period of time

(6 months short course)

o No trials of therapy should be given – once decision

to start Rx has been taken � Rx must be completed

o NTBCP protocols must be followed

Probability of Survival during TB Treatment

0.7

0.75

0.8

0.85

0.9

0.95

1

HIV neg

HIV pos

Pro

babi

lity

of s

urvi

val

0 30 60 100 160 180

DaysNunn P et alAm Rev Respir Dis 1992;146:849-54

3.8

4

4.2

4.4

4.6

4.8

5

5.2

5.4

PRE O.I. POST

Effect of opportunistic infections

Viral load (log10)

(Donovan 1996)

Cotrimoxazole in TB/HIV

0

5

10

15

20

25

30

Mortality Hospitalisation

/100

per

son

year

s

Placebo Cotrimoxazole

Lancet 1999;353:1469

TB & ARV’sthe challenges

1.1. Complex Complex drugdrug--drug interactionsdrug interactions

2.2. Increased Increased pill burdenpill burden

3.3. Shared Shared toxicitytoxicity

4.4. Paradoxical Paradoxical deteriorationdeterioration of TB due to of TB due to

immune reconstitutionimmune reconstitution

Shared toxicity

•• Overlapping toxicity is Overlapping toxicity is commoncommoncommoncommoncommoncommoncommoncommon•• Leads to Leads to difficult managementdifficult managementdifficult managementdifficult managementdifficult managementdifficult managementdifficult managementdifficult management

decisionsdecisions•• Most common shared sideMost common shared side--effects:effects:

–– Peripheral neuropathiesPeripheral neuropathies–– NauseaNausea–– RashRash–– HepatitisHepatitis

Common shared toxicity of HAART and anti TB drugs

TOXICITYTOXICITYTOXICITYTOXICITY TB DRUG/STB DRUG/STB DRUG/STB DRUG/S ARTARTARTART

Peripheral neuropathy INH

Stavudine (d4T)Didanosine (ddI)

Rash RIFINHPZA

NNRTI’s

NauseaPZA

Didanosine (ddI)Zidovudine (AZT)

Protease inhibitors

Hepatitis RIFINHPZA

NNRTI’s

Drug interactions

•• Rifampicin in a powerful Rifampicin in a powerful enzyme inducerenzyme inducerenzyme inducerenzyme inducerenzyme inducerenzyme inducerenzyme inducerenzyme inducer–– enhanced metabolism of PIenhanced metabolism of PI’’s (except s (except

Ritonavir) and to a lesser extent, NNRTIRitonavir) and to a lesser extent, NNRTI’’ss

•• Rifampicin levels are Rifampicin levels are not significantly not significantly affectedaffected by HAARTby HAART

•• Antiretroviral drugs Antiretroviral drugs cancancancancancancancan be used be used concomitantly with Rifampicinconcomitantly with Rifampicin

HAART interactions with Rifampicin

NRTI’s & NtRTI’s No interactions

Efavirenz Non significant reduction in EFV

levels

Nevirapine Significant reduction in NVP

levelsLopinovir/Ritonovir

(400mg/100mg) plus

Ritonovir 300mg

(Can also give double

dose LOP/rit)

No significant interactions

All other PI’s Marked reduction in PI levels -

AVOID

• If TB present before starting ART

– Time of initiation of ARVs depends on CD4 count and

clinical condition (Use efavirenz instead of nevirapine)

•• CD4CD4CD4CD4CD4CD4CD4CD4+ + + + + + + + > 350 > 350 > 350 > 350 > 350 > 350 > 350 > 350 –– does not need ART yet.does not need ART yet.•• CD4CD4CD4CD4CD4CD4CD4CD4+ + + + + + + + < 350< 350< 350< 350< 350< 350< 350< 350 –– delay ART until delay ART until after intensive phaseafter intensive phaseafter intensive phaseafter intensive phaseafter intensive phaseafter intensive phaseafter intensive phaseafter intensive phase

of TB treatment has been completed of TB treatment has been completed unless patient unless patient very ill very ill

•• CD4CD4CD4CD4CD4CD4CD4CD4+ + + + + + + + <100<100<100<100<100<100<100<100 –– delay ART until sure that TB delay ART until sure that TB medication is tolerated, medication is tolerated, after after after after after after after after ±±±±±±±± 2 weeks2 weeks2 weeks2 weeks2 weeks2 weeks2 weeks2 weeks

TB treatment and HAART

Paradoxical worsening of TB

•• More More commoncommoncommoncommoncommoncommoncommoncommon in HIVin HIV--infected patients.infected patients.•• Typical in large Typical in large lymph nodeslymph nodeslymph nodeslymph nodeslymph nodeslymph nodeslymph nodeslymph nodes or CNS or CNS

tuberculomastuberculomastuberculomastuberculomastuberculomastuberculomastuberculomastuberculomas..

•• RRelated to initiation of ARTelated to initiation of ARTelated to initiation of ARTelated to initiation of ARTelated to initiation of ARTelated to initiation of ARTelated to initiation of ARTelated to initiation of ART, especially if , especially if commenced within intensive phase of TB commenced within intensive phase of TB treatment = Immune reconstitution treatment = Immune reconstitution inflammatory syndrome (IRIS)inflammatory syndrome (IRIS)

Mechanism?

•• Host immune responseHost immune responseHost immune responseHost immune responseHost immune responseHost immune responseHost immune responseHost immune response????????–– Increased antigen release Increased antigen release –– TB therapyTB therapy–– Immune reconstitution Immune reconstitution –– ART/HAARTART/HAART

•• In patients who initiate HAART if CD4In patients who initiate HAART if CD4++ < 50< 50

TB Prophylaxis

�� TB prophylaxis leads to 60% decrease of TB prophylaxis leads to 60% decrease of

clinical TB inclinical TB in HIV+ patients with PPD skin test HIV+ patients with PPD skin test

≥≥≥≥≥≥≥≥ 5mm5mm

Efficacy of INH Preventive Therapy among HIV-positive, TST-positive(> 5mm) Persons

0

2

4

6

8

1 0

1 2

H a i t i Z a m b ia U g a n d a K e n y a

TB

rat

e (%

per

yea

r)

I N H P la c e b o

Isoniazid (INH) reduces active TB rate by 60%(but only among TST-positive persons)

Eligibility for TB prophylaxis

• Although the benefit of IPT is greater in people with a positive TST

– Not practical to do TST on all patients

– Many anergic due to immunosuppression

• All HIV+ people not on ART and no features of active TB are eligible

– Screen for TB with good history of symptoms and clinical examination

• Patients with signs and symptoms suggestive of TB must first be investigated for TB (CXR + culture)

WHO IS NOT ELIGIBLE FOR TB PREVENTIVE

THERAPY?

• Active liver disease or active alcohol abuse

• Active TB in past 2 years

• Patients already on ART

• Patients who receive TB preventive therapy

and who require to start HAART

– can complete their TB preventive therapy even if

the ARV treatment is started

– there is no interaction between INH and the

current ART regimens used

RECOMMENDED REGIMEN

• INH: 5 mg/kg/day (maximum 300 mg per day) for 6 months

– Protects against TB for another 12 months

• Additional Pyridoxine to prevent peripheral neuropathy (25 mg od)

• No definite evidence to support other drug regimens

• High risk groups to be targeted

– Miners, Prisoners, Health care workers

HIV infection is the biggest single

challenge to TB control efforts on the

African continent

TB is the biggest single challenge in

reducing HIV/AIDS related morbidity

and mortality on the African continent

Thank youJantjie Taljaard

jjt@sun.ac.za

083 419 1452