HIV AND TB new 2 - Stop TB Partnership · HIV and TB TB is the most common opportunistic infection in HIV infection and the first cause of mortality in HIV infected (10 -30%) 10 millions

Tuberculosis/HIV infectionTuberculosis/HIV infection

Bendayan DanieleBendayan Daniele MDMD

Pulmonary and Tuberculosis Department, Shmuel Harofe Hospital, Pulmonary and Tuberculosis Department, Shmuel Harofe Hospital, IsraelIsrael

HIV and TB HIV and TB

�� TB is the most common opportunistic infection in HIV infection TB is the most common opportunistic infection in HIV infection and the first cause of mortality in HIV infected (10and the first cause of mortality in HIV infected (10--30%)30%)

�� 10 millions patients co infected in the world.10 millions patients co infected in the world.

11% in children ( 85% in SubSaharan Africa )11% in children ( 85% in SubSaharan Africa )

�� Immunosuppression induced by HIV modifies the clinical Immunosuppression induced by HIV modifies the clinical presentation of TBpresentation of TB ::

1.1. Subnormal clinical and roentgen presentationSubnormal clinical and roentgen presentation

2.2. High rate of MDR/XDRHigh rate of MDR/XDR

3.3. High rate of treatment failure and relapse (5% High rate of treatment failure and relapse (5% vsvs << 1% in HIV 1% in HIV -- ))

Case 1Case 1

�� A 33 year old woman, Ukraine origin A 33 year old woman, Ukraine origin

�� Presenting symptomsPresenting symptoms: :

1.1. Fever 39Fever 39°°--4040°°1 month1 month

2.2. Dry coughDry cough-- abdominal painabdominal pain

�� In the pastIn the past::

1.1. 10 years ago:10 years ago:““ pleuritispleuritis”” , pleural punction , pleural punction

2.2. Intra venous drug addictIntra venous drug addict

3.3. HIV test negative 6 years agoHIV test negative 6 years ago

�� Physical examinationPhysical examination::

1.1. Febrile , left pulmonary ronchus Febrile , left pulmonary ronchus

2.2. Enlarged liver firm, non tender (7cm below the Rt costaEnlarged liver firm, non tender (7cm below the Rt costal l

margin ) margin )

Laboratory ResultsLaboratory Results

PLTPLTLYLYPMNPMNWBCWBCHbHbESRESR

291.000291.0001010³³//µµLL

7%7%81 %81 %720072001010³³//µµLL

9 9 g/dlg/dl140140

AlbuminAlbuminProteinProteinCreatinineCreatinineUreaUreaPotassiumPotassiumNatriumNatrium

2.92.9grgr(3.5(3.5--5.5)5.5)

6.96.9 grgr

(6(6--8)8)

0.60.6 mgmg

(0.7(0.7--1.2)1.2)

2929 mgmg

(10(10--45)45)

3.83.8 meq/Lmeq/L

(3.5(3.5——5.1)5.1)

131131meq/Lmeq/L

(135(135--145)145)

PTPT--PTTPTTBilirubineBilirubineSGPTSGPTSGOTSGOTγγ GTGTAlkal Alkal

PhosphPhosph

NN11 mgmg7878 IUIU((99--37)37)

4242 IUIU

(11(11--39)39)

11381138 IUIU19801980 IUIU

(100(100--290)290)

Case 1Case 1

Case 1Case 1

Case 1Case 1

Abdominal CT : Abdominal CT : diffuse hepatic infiltrationdiffuse hepatic infiltration

Needle Core Biopsy: granulomas hepatitis Needle Core Biopsy: granulomas hepatitis

Case 1Case 1

SputumSputumBlood Blood

culturecultureVDRLVDRL

IGgIGg

HCVHCV

AbAbHBs AgHBs AgVLVLCD4CD4

Cells / Cells / µµLL

HIVHIV

(Elisa +WB(Elisa +WB))

AFB+Gene AFB+Gene

probe: probe:

negativenegative

negativenegative++++negativenegative>100.000>100.000495495

(15%)(15%)++

Liver granuloma and FUO in HIV positive patientLiver granuloma and FUO in HIV positive patient

????????????

Granulomatous HepatitisGranulomatous Hepatitis: : 22--15% liver Bx15% liver Bx

Uta Drebber et al. liver international 2008: 828Uta Drebber et al. liver international 2008: 828--834834

Gaya DR et al. J Clin Patho 2003: 850Gaya DR et al. J Clin Patho 2003: 850--3 3

Dourakis SP et al. Euro Dourakis SP et al. Euro J Gastroentrology Hepatol 2007:101J Gastroentrology Hepatol 2007:101--106106

Saudi Saudi

ArabiaArabiaN IrelandN Ireland

63/166263/1662

GreeceGreece

66/176866/1768

GermanGerman

442/12161442/12161

23%23%68%68%48.6%48.6%Primary Primary

Biliary Biliary

CirrhosisCirrhosis

11%11%7.6%7.6%8.3%8.3%SarcoidosisSarcoidosis

55/5955/59

TB:19 casesTB:19 cases

4.8%4.8%3.9%3.9%

TB: 3casesTB: 3cases

infectiousinfectious

9.5%9.5%7.5%7.5%Chronic HCVChronic HCV

9.5%9.5%2.4%2.4%DrugsDrugs

36%36%OtherOther

HIV and Hepatic GranulomaHIV and Hepatic Granuloma

�� Literature : Literature : Tb responsible for most of the casesTb responsible for most of the cases

1.1. retrospective study 1985retrospective study 1985--19971997

Evaluate etiology 93 pts with HIV, FUO and HG . Evaluate etiology 93 pts with HIV, FUO and HG .

TB responsable for all the cases (78%with othTB responsable for all the cases (78%with other site TB)er site TB)

1.1. Liver specimen obtained from 171pts with AIDS Liver specimen obtained from 171pts with AIDS Significant microscopic abnormalities in 58%Significant microscopic abnormalities in 58%

70 pts with TB (35 with anatomical TB lesions70 pts with TB (35 with anatomical TB lesions

Vidal F et al . IntVidal F et al . Int Conf AIDS 1998 12:288 Conf AIDS 1998 12:288

Lanjewar DN . HIV 20Lanjewar DN . HIV 2004:25304:253--77

�� Hepatic tuberculosis is associated with 90% cases of miliary TBHepatic tuberculosis is associated with 90% cases of miliary TB

�� Tubercule bacilli reach the liver by way of hematogenous Tubercule bacilli reach the liver by way of hematogenous dissemination: Hepatic artery in case of miliary tuberculosisdissemination: Hepatic artery in case of miliary tuberculosis

Portal vein in case of focal liver tuberculosisPortal vein in case of focal liver tuberculosis

Case 1 Case 1

�� Antituberculosis treatment (INH, RFP, PZA ETB) progressive Antituberculosis treatment (INH, RFP, PZA ETB) progressive elevated doses elevated doses

�� Fever decreased dramatically and abdominal pain improvedFever decreased dramatically and abdominal pain improved

�� Progressive improvement in liver function Progressive improvement in liver function ((Alk phosph decreased from 1980 IU to 200 IU )Alk phosph decreased from 1980 IU to 200 IU )

�� Positive Tuberculosis Cultures : sputum and urinePositive Tuberculosis Cultures : sputum and urine�� Non Caseiting granuloma in liverNon Caseiting granuloma in liver

�� Dg : Generalized Tuberculosis and AIDSDg : Generalized Tuberculosis and AIDSDg : Generalized Tuberculosis and AIDSDg : Generalized Tuberculosis and AIDSDg : Generalized Tuberculosis and AIDSDg : Generalized Tuberculosis and AIDSDg : Generalized Tuberculosis and AIDSDg : Generalized Tuberculosis and AIDS(reactivation of old untreated TB) (reactivation of old untreated TB) (reactivation of old untreated TB) (reactivation of old untreated TB) (reactivation of old untreated TB) (reactivation of old untreated TB) (reactivation of old untreated TB) (reactivation of old untreated TB)

Tuberculosis Treatment and HAARTTuberculosis Treatment and HAART

�� Active TB is an AIDSActive TB is an AIDS--defining disease defining disease

�� Begin anti TB treatment immediately Begin anti TB treatment immediately Duration of Anti TB treatmentDuration of Anti TB treatment 9 months to 1 year9 months to 1 year

�� HAART TimingHAART Timing : : no consensusno consensus

>200 cells/mm : defer until complete TB treatment>200 cells/mm : defer until complete TB treatment

>50 cells/mm and < 200 cells/mm: wait until induction p>50 cells/mm and < 200 cells/mm: wait until induction phasehase

< 50 cells/mm : start as soon as possible< 50 cells/mm : start as soon as possible

�� ProblemsProblems::

Drug toxicities (skin rash, hepatotoxicity)Drug toxicities (skin rash, hepatotoxicity)

Drug interaction RFP decreases level of ARV drugDrug interaction RFP decreases level of ARV drug-- resistanceresistance

Immune restoration induced by HAART may be associatImmune restoration induced by HAART may be associated with IRISed with IRIS

Use of HAART results in marked decreases of death and Use of HAART results in marked decreases of death and otherother opportunistic infectionopportunistic infection

Anti Retroviral TreatmentAnti Retroviral Treatment

�� A retrospective series from England :A retrospective series from England :

�� 188 patients188 patients : : 85% no antiretroviral85% no antiretroviral--therapy when TB was therapy when TB was

diagnosed diagnosed

45% began HIV therapy during TB 45% began HIV therapy during TB treatment treatment

(median of 2 months after TB dia(median of 2 months after TB diagnosis).gnosis).

�� 3.5%: new AIDS3.5%: new AIDS--defining illnesses (defining illnesses (compared with 24% in those not compared with 24% in those not treated). treated).

�� 50% Adverse Events (. peripheral neuropathy, rash, hepatitis, an50% Adverse Events (. peripheral neuropathy, rash, hepatitis, and d GI) GI)

�� 30% either changed or interrupted TB or HIV treatment. 30% either changed or interrupted TB or HIV treatment.

�� 16 coinfected patients who died did not receive antiretrovirals16 coinfected patients who died did not receive antiretrovirals

Dean GL et al. AIDS. 2002;16:75Dean GL et al. AIDS. 2002;16:75--8383

Anti Retroviral treatmentAnti Retroviral treatment

�� Reverse Transcriptase inhibitorReverse Transcriptase inhibitor ::

interferes with the reverse transcription that converts HIV RNA interferes with the reverse transcription that converts HIV RNA to HIV DNAto HIV DNA

1.1. NRTI nucleoside analogue (AZT, lamivudine)NRTI nucleoside analogue (AZT, lamivudine)

2.2. NNRTI non nucleoside analogue . (NNRTI non nucleoside analogue . (Nevirapine )Nevirapine )

�� Pi: Protease InhibitorPi: Protease Inhibitor

prevents maturation of virion capable of infecting other cellsprevents maturation of virion capable of infecting other cells

( Indinavir, Ritonavir)( Indinavir, Ritonavir)

�� Treatment combinationTreatment combination (HAART)(HAART)

2NRTI AND NNRTI 2NRTI AND NNRTI � �(EFV or NVP)1(EFV or NVP)1stst line line

3 NRTI 3 NRTI -- alternative 1alternative 1stst lineline

2NRTI and PIr (SQV/r2NRTI and PIr (SQV/r or LPV/r and RTV or LPV/r and RTV –– 22ndnd lineline

�� Since the use of HAART, mortality from HIV has declined dramaticSince the use of HAART, mortality from HIV has declined dramatically in ally in the developed worldthe developed world..

HAART and TB : PROBLEMSHAART and TB : PROBLEMS

�� Toxicities:Toxicities:

1414--20% of HIV+ pts starting ARV have elevation in Liver function 20% of HIV+ pts starting ARV have elevation in Liver function tests tests 22--10% need to interrupt ART because of significant hepatotoxicity 10% need to interrupt ART because of significant hepatotoxicity CNS (EFV) CNS (EFV) Skin rash (NVR)Skin rash (NVR)

•• Drug interactionDrug interaction::

Regimen including Regimen including RifampicinRifampicin reduce the therapeutic activity of NNRTI and PI through thereduce the therapeutic activity of NNRTI and PI through thecytochrome P450 enzymecytochrome P450 enzyme

Lead to HIV resistance Lead to HIV resistance

WHO recommendation: regimen containing EFV (WHO recommendation: regimen containing EFV (2NRTI AND NNRTI )2NRTI AND NNRTI )

�� Immune reconstitution syndrome (IRIS)Immune reconstitution syndrome (IRIS)

1.1. TB IRIS is characterized by clinical worsening soon afterTB IRIS is characterized by clinical worsening soon after initiation of ARTinitiation of ART

2.2. Occurs in Occurs in 1010--30%30% of patients commencing ARTof patients commencing ART

3.3. Cause: recovery of the immune system after HAART institutioCause: recovery of the immune system after HAART institution with reconstitution of antigenn with reconstitution of antigen--

specific T cellspecific T cell--mediated immunitymediated immunity

Important to differentiateImportant to differentiate from treatment failurefrom treatment failure

Case 1Case 1

�� After 2 months of anti TB treatment, new test for CD4 : After 2 months of anti TB treatment, new test for CD4 :

we begun on HAART we begun on HAART ((CD4 fall from 495 to 35 cellsCD4 fall from 495 to 35 cells/ / µµL)L)

�� No hepatotoxicity, Mild gastrointestinal troublesNo hepatotoxicity, Mild gastrointestinal troubles

�� Few weeks after ARV treatment:Few weeks after ARV treatment:

Fever 39Fever 39

Blood culture negativeBlood culture negative

Xray : no changeXray : no change

�� IRIS Steroid treatment for 1 month: improvementIRIS Steroid treatment for 1 month: improvement

�� The pt is ongoing with both treatment The pt is ongoing with both treatment

Conclusion (Case 1)Conclusion (Case 1)

�� In HIV positive patient with fever, liver infiltration and In HIV positive patient with fever, liver infiltration and

Hepatic Granuloma, Hepatic Granuloma, Tuberculosis infection is highly Tuberculosis infection is highly

suspected suspected

�� Anti TB treatment should be institute rapidlyAnti TB treatment should be institute rapidly as the as the

diagnosis may be delayeddiagnosis may be delayed

�� Actually, HAART and anti TB is safeActually, HAART and anti TB is safe and reduces mortality and reduces mortality

especially if EFV regimen usedespecially if EFV regimen used

�� IRIS IRIS isis frequent frequent

Case 2Case 2

�� 33 year old man born in Ethiopia33 year old man born in Ethiopia

�� One year ago, hospitalized One year ago, hospitalized

because of increased dyspnea because of increased dyspnea

and hypoxiaand hypoxia

�� Work up revealed Work up revealed

1.1. HIV positivity CD4 =200 cells/ HIV positivity CD4 =200 cells/ µµLL

1.1. BAL : PCP pneumonitis BAL : PCP pneumonitis

2.2. Cotrimoxazole (septrin) 21 daysCotrimoxazole (septrin) 21 days

and prednisoneand prednisone

1.1. improvement improvement

�� Non compliance Non compliance --no follow up no follow up

Case 2Case 2

�� Few months later, he complained :Few months later, he complained :

cough, dry sputumcough, dry sputum

dizziness worsening headache,dizziness worsening headache,

deviation of the walk on the left side deviation of the walk on the left side

No confusion, no feverNo confusion, no fever

�� Physical examination:Physical examination:

Looks very sick, cachexiaLooks very sick, cachexia

Cervical lymph nodesCervical lymph nodes

Bilat firm pruritic nodules on the arms and legs Bilat firm pruritic nodules on the arms and legs

�� Laboratory examination : Laboratory examination :

CD4 : 26 cells / CD4 : 26 cells / µµL L

Sputum negative for AFB in ZN stainSputum negative for AFB in ZN stain

Case Report (2)Case Report (2)

�� Cerebro Spinal Fluid: clear colorless Cerebro Spinal Fluid: clear colorless

normal opening pressure, normal opening pressure, protein normal protein normal

glucose : 100 mg glucose : 100 mg -- no pleocytosis no pleocytosis

�� Differential Diagnosis:Differential Diagnosis:

1.1. Infectious (Infectious (Cryptococcal toxoplasomosis, CMV, Nocardia, Cryptococcal toxoplasomosis, CMV, Nocardia,

MTB) MTB)

1.1. Malignancy Malignancy –– Lymphoma Lymphoma

�� Skin biopsy: Skin biopsy: prurigo nodularisprurigo nodularis ((epidermal proliferationepidermal proliferation))

�� LN biopsy: LN biopsy: caseiting granulomacaseiting granuloma

Anti TB treatment ( INH, RF, ETB, PZA) and HAART (EFV regimenAnti TB treatment ( INH, RF, ETB, PZA) and HAART (EFV regimen) )

Extra Pulmonary TBExtra Pulmonary TB

�� Very frequent in HIV infected people (50% /15%)Very frequent in HIV infected people (50% /15%)

�� Related to the degree of immunosuppression (>70% when CD4< 200)Related to the degree of immunosuppression (>70% when CD4< 200)

�� Children : high frequency of meningitis and progressive diseaseChildren : high frequency of meningitis and progressive disease

Key points 1Key points 1

�� Tuberculosis is the major cause of morbidity and mortality in HTuberculosis is the major cause of morbidity and mortality in HIV IV

infectedinfected

�� HIV increased the rate of progression and reactivation of TB HIV increased the rate of progression and reactivation of TB

�� HIV modifies the presentation of TB and make diagnosis difficultHIV modifies the presentation of TB and make diagnosis difficult

with a high frequency of EPTBwith a high frequency of EPTB

�� TB accelerates the progression of HIV (TNF )TB accelerates the progression of HIV (TNF )

All HIV infected should be evaluated for TBAll HIV infected should be evaluated for TB

All TB infected should be offered HIV testAll TB infected should be offered HIV test

Key points 2Key points 2

�� Treat TB before over initiating HAARTTreat TB before over initiating HAART

�� Rifampicin has significant drug interaction with ARV drugsRifampicin has significant drug interaction with ARV drugs

�� Understand paradoxical reactionUnderstand paradoxical reaction

�� Identify drug resistanceIdentify drug resistance

�� High suspicion, early institution of anti TB drugs and close High suspicion, early institution of anti TB drugs and close

monitoring is the monitoring is the key to successful managementkey to successful management

Thank you Thank you !!!!!!!!

Child / Adult TB/HIV Child / Adult TB/HIV

�� Tuberculosis infection Tuberculosis infection

children recent transmission children recent transmission

adult reactivationadult reactivation

�� Incidence : Incidence :

Children vs adults Low incidence in well controlled TB countrChildren vs adults Low incidence in well controlled TB countryy

20 fold increase TB incid20 fold increase TB incidence in HIV + / HIV ence in HIV + / HIV ––

�� High rate of mortality and morbidityHigh rate of mortality and morbidity

�� Disease severity: Disease severity: age (<3 years) life threatening manifestationsage (<3 years) life threatening manifestations

immune statusimmune status

�� Diagnosis: Diagnosis: close contact+ TST+ Xray (IGRA)close contact+ TST+ Xray (IGRA)