TB and HIVand OIs

Dr A.L. Pozniak

Chelsea and Westminster HospitalLondon, UK

2

OI: A syndromic approach

• Short of breath• Diarrhoea• Difficulty swallowing• “Stroke”• Meningitis• Dementia• Eye problems• Constitutional

4

Dyspnoea

•Commonest cause bacterial pneumonia

Infectious Causes of Respiratory Disease

• 1.Bacteria - S. pneumoniae- H. influenzae- Pseudomonas

• 2.Mycobacteria - Tuberculosis• - MAI• - Other • mycobacterium

• 3.Viral CMV• EBV

• 4. FungalCandida

• -Aspergillus• -Histoplasmosis• -PCP

• 5. Protozoa• -Cryptosporidia• -Toxoplasmosis

PCP

•20-50% normal CXR•10% consolidation•Typically appears like pulmonary oedema

•SOB on exertion•No physical signs

7

Radiology of PCP

Diagnosis of PCP

•Blood gases (not diagnostic but prognostic)

•Induced sputum/bronchoscopy

•Mainly presumptive

PCP treatment - first line

•Cotrimoxazole 3860mg bd• Hypersensitivity• Stevens-Johnson syndrome• Nausea• Hepatitis• Bone marrow suppression•PaO2 <7.5 kPa add steroids (Methylprednisolone iv 40mg qds or Prednisolone po 40mg od 5 days)

PCP treatment – second line

• 3 Options:• 1. Pentamidine 4mg/kg i.v.daily

• 2.Trimethoprim 15mg/kg iv/po daily & dapsone 100mg po bd

• 3.Clindamycin 600mg iv/po qds & primaquine 15-30mg po od

• 4.Casperfungin?

11

Pulmonary nodules

•KS•Miliary TB•Lymphoid interstitial pneumonitis

Acute diarrhoea

Acute

Bacterial

Viral

Ciprofloxacin(ampicillin resistance)

Salmonella

Campylobacter

Shigella

Rotavirus etc

Long term maintenance

13

Chronic diarrhoea

Chronic

Cryptosporidium

Microsporidium

Auramine

Biopsy & stain

Treatment: HAART

Difficulty swallowing

Mouth

Candida

Fluconazole(Itraconazole if resistant)

No candida

Apthous

CMV (CD4 <50/mm3)

Herpes (rare)

15

Gastroscopy rarely necessary

CMV oesophagitis

CNS Disease in HIVMass Lesions 1° cerebral lymphomaToxoplasmosisPMLCMVTuberculosisCryptococcusAspergilloma

Diffuse EncephalitisCMVHSVHZV

“Stroke” syndrome

• Big 3• Toxoplasmosis• Cerebral lymphoma• Progressive multifocal leukoencephalopathy

• Rarities• Cryptococcoma• Tuberculoma• Aspergilloma• Arteritis• Tumour/metastases• Abscess

CT scan appearances

DIAGNOSIS CT SCAN

Toxoplasmosis Multiple, ring-enhancing

Cerebral lymphoma

Little enhancement

PML White matter changes

Toxo Lymphoma PML

Toxoplasmosis -treatment

Sulphadiazine 2g qdsPyrimethamine 75mg od Folinic acid 15my od

Clindamycin 600mg qdsPyrimethamine 75mg od Folinic acid 15my od

Steroids to reduce mass effect

Sulphonamide allergyLong-term maintenance

Meningitis

• Viral• Bacterial (including TB)• Fungal (Cryptococcus)• Neoplastic

Meningitis algorithm

Lumbar puncture

Normal glucoseLymphocytes

Viral

Low glucose

No papilloedema or focal neurology

TB (lymphocytes)

Cryptococcus (antigen)

Neoplastic (cells)

Bacteria (polymorphs)

OrganismsNB Measure opening pressure and repeat if high

24

Cryptococcal meningitis treatment

Obtunded Well

Amphotericin(renal & marrow toxicity)

Fluconazole 400mgMaintenance & HAART

5-Fluorocytosine may increase rateOf clearance of cryptococcus

Fluconazole 400mg bd

Maintenance untilCD4>100 / 6months

25

Eye problems

CMV (CD4 <50/mm3)

Toxoplasma

Rarities

Vitreous haemorrhage

Retinal detachment

Infections (TB, PCP)

Tumours

26

CMV retinitis treatment

•HAAART•and•Ganciclovir•Valganciclovir•Cidofovir

Constitutional symptoms

FeverWeight Loss Look everywhere Lymph nodes

Mouth

Skin

EyesDifferential diagnosis

SepsisTB MAI (CD4 <50/mm3)Lymphoma (LDH, CT if available)

28

MAI

•Anaemia•Weight loss•Fever•Abdominal pain / hepatomegally•CD4 <50/mm3

•Raised Alk Phos

MAI treatment

• HAART• and• Rifabutin• Clarithromycin• (Steroids)

Resistance develops rapidly

HIV wasting

•“Slim disease”•Usually OI •(oesophageal candida, cryptosporidiosis)

When to start HAART-ACTG A5164: Immediate vs Deferred ART in Patients With Acute OIs

Zolopa A, et al. CROI 2008. Abstract 142.

Immediate Antiretroviral TherapyInitiation within 48 hours of randomization and

within 14 days of starting OI treatment(n = 141)

Deferred Antiretroviral TherapyInitiation between Weeks 4 and 32

(n = 141)

HIV-infected patients receiving

treatment for presumed or

confirmed acute OI/BI*

(N = 282)

Stratified by CD4+ cell count < or 50 cells/mm3, PCP, BI, or other OI

48 weeks

48 weeks

*Patients with TB excluded.

ACTG A5164: Improved Outcomes With Immediate ART During Acute OI 92% treatment naive

– Median baseline CD4+ cell count 29 cells/mm3; HIV-1 RNA 5.07 log10 copies/mL

OIs with effective antimicrobial therapy only: PCP, bacterial infections, cryptococcal disease, MAC, toxoplasmosis

Median duration from start of OI treatment to initiation of HAART

– Immediate group: 12 days

– Deferred group: 45 days Week 48 virologic outcomes

similar between groups Safety and incidence of IRIS

similar between groupsZolopa A, et al. CROI 2008. Abstract 142.

Patie

nts

Prog

ress

ing

to A

IDS

or D

eath

at W

eek

48 (%

)

100

80

60

40

20

0

14.224.1

Immediate Deferred

P = .035

TB and HIV

Estimated CasesEstimated Deaths

All Forms TB 8.8 million 1.6 Million

MDRTB 424,000 116,000

XDR-TB 27,000 16,000

Global TB Estimates (2006)

35

TB

•More dissemination•Less cavitation•More blood culture positive

•Not every abnormal CXR is TB, treat for bacterial pneumonia first

TB/HIVMany Challenges

• Diagnosis of active or Latent TB• Chemopreventative therapy

• When to start Antiretroviral Therapy (ART)• What ART to start • Second Line ART during TB treatment • Drug interactions• Immune Reconstitution• XDR TB

Inability of the PPD in distinguishing active TB from inactive infection

Active TB

TB contacts

Latent TBinfection

Distribution of induration sizes of the tuberculin (10 IU) skin test healthy young students in

France

0

10

20

30

40

50

60

Num

ber o

f sub

ject

s

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15Induration size of the tuberculin skin test (mm)

n = 435n = 435

Distribution of induration sizes of tuberculin (10IU) skin test in HIV+ & TB+ subjects in France

0

5

10

15

20

25

Num

ber o

f sub

ject

s

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16Induration size (mm)

n = 49n = 49

Abandon PPD?In HIV patients.. In developing world • Screen for active tb with history and chest Xray give all rest Isoniazid chemoprophylaxis

• Don’t screen but give all asymptomatic patients Isoniazid chemoprophylaxis

• In developed world Give INH until CD4 is over 200

What else can we use?Gamma Interferon assays

Blood test looking for T cell response to Specific MTB antigen Recommended by CDC and NICE UK

Not yet approved for HIV-infected persons

Need technical expertise and costly but cost effective

T-SPOT.TB performance in HIV-1 patients is comparable to that reported in immune competent patients

Patient Group Sensitivity Specificity

Immune Competent * 83-97% 97% -100%

All HIV patients with active TB 89% 100%

HIV patients CD4 < 300 cells/ul

HIV patients CD4 < 200 cells/ul

HIV patients CD4 < 100 cells/ul

90%

88%

78%

100%

100%

100%

*Am J Resp Crit Care Med 2006 174;736-742

No correlation between CD4 T cell count and magnitude of TB antigen responses

8006004002000

CD4 T cell count (cells/ul)

2500

2000

1500

1000

500

0

No.

TB

ant

igen

spe

cific

T c

ells

/ 10

^6 P

BM

C’s

>300<300

HIV patients with positive ELISPOT stratified according to CD4 T cell count (cells/ul)

2500

2000

1500

1000

500

0

No

TB a

ntig

en s

peci

fic T

cel

ls /

10^6

PB

MC

's

n = 29 n = 15

TB/HIV interferon gamma

? Effect of CD4? Extrapulmonary TB? More indeterminates? Do they go negative with treatment?any quantitative differences comparing active with latent tb

TB prevention-use HAART!

• Many still like the INH prophylaxis plan –• How useful is it?• How practical is it?

0.05 .1 .2 .3 .4 .5 1 2 3 4 5 10 20

Favours isoniazid Favours controlTuberculin skintest positive patients

INH for TB/HIVTuberculin skin test positive patients

All Studies

Risk ratio & 95% CI

1

2

4

5

3

study

0.05 .1 .2 .3 .4 .5 1 2 3 4 5 10

Favours isoniazid

Risk ratio & 95% CI

Favours controlTuberculin skintest negative patients

Isoniazid (INH) for TB/HIVTuberculin skin test negative patients

All Studies

1

2

3

5

4

study

1995Uganda

1995Rwanda

1995 Zambia

1997Thailand

1998Uganda

1999Brazil

HIV seroprevalence

in study population (%)

HIV+ persons

entering the PT process

(%)

Those entering the process who started PT

(%)

235347

100100100

Adherence(%)Year Country

159534

10051

100

301238893875

62--

697061

Proportion of Individuals Dropping Out of Preventative Therapy (PT) in

Feasibility Studies

clinicaloptions.com/hiv

-0.5

0.5

1.5

2.5

3.5

4.5

5.5

1 2 3 4 5

TB Incidence During HAART

P trend = .02

Years of HAART

TB In

cide

nce

Rat

e (C

ases

/100

PYs

)

Impact of HAART on Incidence of TB in HIV-Infected Adults

Lawn S, et al. CROI 2006. Abstract 68.

Adults

Initial reduction in TB incidence 11% to 3%

Incidence remained low over 5 years but still 1% per annum on HAART

Effect of CD4 count on risk of TBamong HIV-infected people

0

5

10

15

20

Italy US South Africa

>350 200-350 <200

Incidence of TB (per 100 pyrs)

Antonucci JAMA 1995;274:143; Markowitz Ann Int Med 1997;126:123; Badri Lancet 2002;359:2059

Issues in initiating antiretroviral therapy in

HIV patients with TB

Treatment of drug sensitive TB

• 90% of MTB dead in 2 days when regimen includes INH

• 99% of MTB dead in 14 days when regimen also includes RIfampicin

• If INH and RIF and PZA given in first 2 months then total course of TB treatment is 6 months

• Debate whether HIV + should be treated for longer

• ? Quinolones will shorten to 4 months

If we are treating both HIV and TB..

• Have we enough evidence to give clear treatment recommendations for HIV and TB coinfection?

• What are the major drug issues for clinicians

• 1. NNRTIs and rifampicin• 2. Pis and rifampicin and rifabutin

Rifampicin

• The major problem is the use of rifampicin with HAART

• But at present it is an essential part of the solution for TB

Wilson. PXR, CAR, and drug metabolism. Nat Rev Drug Disc 2002

CYP3A4 Regulation

• PXR: pregnane X receptor; RXR: retinoid X receptor

• In vitro models now exist for identifying drugs that bind PXR

Drug-drug interactions TB/HIV

Metabolism

Absorption

Elimination

Metabolism

Rifampicin

↑↑CYP3A4

PIs

NNRTIs

Rifampin Effects on HIV Drugs• Protease inhibitors

– Boosted PIs should not be used with concomitant rifampicin-PK or safety or can they?

• Nonnucleoside reverse transcriptase inhibitors (NNRTI)– Nevirapine 37 % decrease what dose?– Efavirenz 26 % decrease what dose?

• Reverse transcriptase inhibitors– No significant effectEnfurvitide- No effect

Rifampin – NVP standard dose case series from HIVNAT pK Lab (n=60)

David Burger; 2005 BKK Symp HIV Med, data provided by Saskia Autar

Nevirapine + Rifampicin

02468

10121416

0 3 6 9 12 15Time (h)

NVP

con

c.

85% of NVP levels in therapeutic range

N=32, ARV naïve, TB/HIV, smear pos, CD4<200, RIF 2-6 weeks

2 weeks 4 weeks 12 weeks

Prospective, randomized, multicenter, open-label, 2-arm study

TDM of NVP

12 hr of NVP

+Assessments:

++

+

48 weeks14 days2-6 weeks of

TB treatment

24weeks interim analysis

Arm 1: NVP 400 mg/day ( GPOvir Z 1 tab po BID)( GPOvir Z 1 tab po BID)Lead in 14 days with NVP 200 QD

Arm 2: NVP 600 mg/day ( GPOvir Z 1 tab po BID+ NVP 1tab QD)( GPOvir Z 1 tab po BID+ NVP 1tab QD)Lead in 14 days with NVP 200 BID

All patients received AZT+3TC as a

backbone

24-Week Efficacy and safety of Nevirapine: 400 mg versus 600 mg based HAART in HIV-infected Patients with Active Tuberculosis Receiving Rifampicin W. Manosuthi1et al IAS2007

23

78.6

33.3

10918.8

0

20

40

60

80

100

Arm 1: NVP400 mg/dayArm 2: NVP 600 mg/day

% p

atie

nts

%

Week 2 Week 4 Week 12N = 14 16 13 11 12 10P-value 0.002 0.596 0.323

Proportion of c-min NVP < 3.1 mg/L

*p=<0.05

Summary of adverse events

* disseminated MAC, bloody pleural effusion and liver mass ** cardiomyopathy and heart failure

***

Efavirenz

• PK data• Standard dose?• Increased dose?

Population PK modeling in HIV-pts with TB treated with EFV and rifampicin

Soy et al. 2005

• • EFV dose 30% increase (from 600 to 800) adequate

• Body weight important determinant on CL

PK of EFV 800 mg plus rifampicin similar to those of EFV 600 mg without rifampicin

Lopez-Cortes et al. 2002

EFV levels in HIV-infected Thai patients with TB

% o

f pat

ient

s

0102030405060

< 1 1-4 > 4

Manisuthi et al. 2005600mg 800mg

Nevirapine and Efavirenz

• What is also important is

• Clinical outcome• Toxicity

18 month outcomes

• 1,283 started ART while on rifampicin: • 209 people on nevirapine and 1,074 on

efavirenz. • Those starting NVP with TB rx had a OR(CI)

of 2.9(1.8-4.7) of virological failure <400 copies compared with those on EFV or not on TB RX

Bollue 38th World Lung Health Conference 2007

Boosted PIs and Rifampin Interaction

Lopinavir/rit

•Ritonavir 400 bid required•GI toxicity and lipid perturbation•High rates of elevated transaminase1 (5/7 dropouts) 1/10 low trough concentrations

plus recent Pk study2

-LFT problems

Saquinavir/rit

1La Porte, AAC, 2004Berger pkw2007

•Early studies from SA suggested could be used •SQV 1000/rit100 BID•39% hepatitis•Transaminase elevations 20x upper normal2

2Roche Dear Doctor, 2005

HAART Dose TB Dose therapy

4NRTI No change RIF No changenevirapine 200 mg bd RIF 600 mg odnevirapine 300 mg bd? RIF 600 mg odefavirenz* 6-800 mg od RIF 600 mg od

TB Treatment RegimensRIFAMPICIN / HAART

*Dose adjusted?

Rifabutin• As “potent” as rifampicin but no long-term data for comparison

CYP3A4 CYP3A4Rifabutin

Active metabolites (i.e. 25-O-desacetyl,

31-hydroxy)

• CYP3A4 inhibitors increase rifabutin levels

Can be administered With PIs

Given at a dose of 150mg 3xWK

Expensive! Cost of 4 days of rifabutin = cost of an entire rifampin regimen

Toxicity: marrow suppression, arthralgias, uveitis

Dosing: Dose adjustments of ART regimens ? Dose with boosted PIs

Benefits Limitations

What about Rifabutin?

TB Treatment RegimensRifabutin

HAART Dose TB Dose therapy

4NRTI No change RBT No changeBoosted PI No change RBT 150? mg 2-3/7nevirapine 200 mg bd RBT 300 mg odefavirenz 600 mg od RBT 450 mg od

PI Rifampicin Rifabutin Comment

TMC 125

Little change use normal doses

TMC 278

APV AUC by 82%AUC, Cmax and Cmin decr by 80/69/89%;

Cmin by 49% Avoid co-adm. with rifampicin\?double dose 278 with rbt

Ral reduced the Cmin AUC and C max of MK-0518 by 61%, 40% and 38% respectively

?Avoid co-adm. with rifampicin

GS 9137

Not done Not done

MRV 6.6-fold increase in CYP3A4 induction with rifampin

Double dose of maraviroc will compensate

DRV Not done

T20 No change No change Can use

r = ritonavir; AUC = area under the curve; Cmax and Cmin= maximum and minimum concentrations; TDM = therapeutic drug monitoring

Newer HIV drugs

When to Start ART: in TB Immediately?

TB, HIV+CD4<350Or ?<200

TB TREATMENT

ANTIRETROVIRAL THERAPY-WHEN?

Months

1 2 6

Don't wait until its too late

• In Patients presenting with Ois including tuberculosis it is important to start ARVs as soon as is practicable

• Toxicity, adherence and IRIS are important but outweighed by the morbidity and mortality in those that dont start HIV treatment

Don’t Wait till it’s too lateFurther AIDS

27/188 TB/HIV patients developed further AIDS

On HAART =3Not on HAART= 24 median CD4 70 cells 90% had median CD4 <100 4 months post TB

16 died only 4 on HAART (3 short term) Dean et al AIDS 2001

a)

Mortality among patients with prevalent Mortality among patients with prevalent active TB (n=73) initiating ARTactive TB (n=73) initiating ART

Awaiting ARTAwaiting ARTARTART

0.50

0.60

0.70

0.80

0.90

1.00

0 30 60 90 120 150 180Days from TB diagnosis

Surv

ival

pro

babi

lity

No difference in CD4 count or Stage 4 disease between those starting and not starting

HIV/TB

What is IRIS?

How is it diagnosed?

How is it managed?

IRIS• Worsening of original disease • No evidence of bacteriological relapse

or recurrence*• May have high fevers – must exclude

concomitant disease • Related to start of ARV not to TB Rx• Often prolonged

* NB not always the case

HIV/TB

 Presenting features of IRIS n

Lymphadenopathy 12Fever 8Sternal skin lesion 2Spleen micro abscesses 1Gluteal abscess 1

Michaelidis AVT 2005

HIV/TBFactor IRIS Non-IRIS pN 14 41Baseline CD4 (cells/mm3) 80 (33 – 117) 139 (77 – 284 )0.050

Baseline CD4 < 100 11 (78.6) 16 (39.0) 0.011Baseline CD4 100 3 (21.4) 25 (61.0)

%Disseminated TB 8 (57) 7(17) 0.006

Fold change in CD4 count 1.5 0.7 0.046from baseline to 3 months (0.6 to 5.6) (-0.2 to 1.0)

Michaelidis AVT 2005

Cytokine gene SNP alleles are associated with immune restoration diseases

Non-HIV(N = >100)

HIV, Non-IRD(N = 33)

Herpesvirus(N = 25)

Mycobacterial(N = 11)

HCV(N = 13)

= IL-6 -174*C = TNFA-308*2 = IL-12-3’UTR*2 = IL-12-promoter*2

Price P et al, AIDS 2002,16:2043

*

*

*

* p<0.05(Compared with non-HIV controls)

Management of immune restoration disease

• Suppression of inflammatory response by corticosteroid therapy– Treatment (DTH > CD8+ T-cell response?)– Pre-emptive? (randomised controlled trials)

• Recurrent aspiration

• Immunomodulatory therapy - May respond to steroids /IL-2 and GM-CSF,OH

Chloroquine,NFkb receptor antaganist

• Cease/modify antiretroviral therapy

Other IRIS-types Unmasking of TB by HAART

• Problem for developing world HAART programs

• Potential for TB drug resistance if patients given INH prophylaxis when start HAART

• ? Screen patients for active TB-CXR may be normal and TST or Elispot won’t differentiate from latent TB

• MDR-TB = Resistance to at least Rifampicin and Isoniazid

• XDR-TB = MDR-TB plus resistance to:– a fluoroquinolone and – >1 of 3 injectable second-line drugs capreomycin, kanamycin,

amikacin(New definition agreed October 2006)

CausesPoor treatmentLack of resistance surveillanceInfection control

Definition of XDR-TB

Countries with confirmed XDR-TB

The bulk of the problem of XDR-TB resides in those countries with high numbers of MDR-TB and two thirds of MDR is in just 3 countries - China, India and the Russian Federation.