TB and HIV and OIs

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TB and HIVand OIs

• Dr A.L. Pozniak
• Chelsea and Westminster Hospital
• London, UK

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(No Transcript)
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OI A syndromic approach

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

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Dyspnoea

• Commonest cause bacterial pneumonia

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Infectious Causes of Respiratory Disease

• 1.Bacteria - S. pneumoniae
• - H. influenzae
• - Pseudomonas
• 2.Mycobacteria - Tuberculosis
• - MAI
• - Other
• mycobacterium
• 3.Viral CMV
• EBV

• 4. Fungal Candida
• -Aspergillus
• -Histoplasmosis
• -PCP
• 5. Protozoa
• -Cryptosporidia
• -Toxoplasmosis

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PCP

• 20-50 normal CXR
• 10 consolidation
• Typically appears like pulmonary oedema
• SOB on exertion
• No physical signs

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Radiology of PCP
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Diagnosis of PCP

• Blood gases (not diagnostic but prognostic)
• Induced sputum/bronchoscopy
• Mainly presumptive

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PCP treatment - first line

• Cotrimoxazole 3860mg bd
• Hypersensitivity
• Stevens-Johnson syndrome
• Nausea
• Hepatitis
• Bone marrow suppression
• PaO2 lt7.5 kPa add steroids (Methylprednisolone
  iv 40mg qds or Prednisolone po 40mg od 5 days)

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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?

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Pulmonary nodules

• KS
• Miliary TB
• Lymphoid interstitial pneumonitis

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Acute diarrhoea
Salmonella
Ciprofloxacin (ampicillin resistance)
Bacterial
Campylobacter
Shigella
Acute
Long term maintenance
Viral
Rotavirus etc
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Chronic diarrhoea
Auramine
Cryptosporidium
Chronic
Biopsy stain
Microsporidium
Treatment HAART
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Difficulty swallowing
Mouth
No candida
Apthous
Candida
CMV (CD4 lt50/mm3)
Fluconazole (Itraconazole if resistant)
Herpes (rare)
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Gastroscopy rarely necessary
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CMV oesophagitis
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CNS Disease in HIV

• Diffuse Encephalitis
• CMV
• HSV
• HZV

• Mass Lesions
• 1 cerebral lymphoma
• Toxoplasmosis
• PML
• CMV
• Tuberculosis
• Cryptococcus
• Aspergilloma

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Stroke syndrome

• Big 3
• Toxoplasmosis
• Cerebral lymphoma
• Progressive multifocal leukoencephalopathy
• Rarities
• Cryptococcoma
• Tuberculoma
• Aspergilloma
• Arteritis
• Tumour/metastases
• Abscess

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CT scan appearances
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Toxo
Lymphoma
PML
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Toxoplasmosis -treatment
Sulphadiazine 2g qds Pyrimethamine 75mg od
Folinic acid 15my od
Long-term maintenance
Sulphonamide allergy
Clindamycin 600mg qds Pyrimethamine 75mg od
Folinic acid 15my od
Steroids to reduce mass effect
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Meningitis

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

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Meningitis algorithm
No papilloedema or focal neurology
Lumbar puncture
Low glucose
TB (lymphocytes)
Normal glucose Lymphocytes
Cryptococcus (antigen)
Neoplastic (cells)
Viral
Bacteria (polymorphs)
Organisms
NB Measure opening pressure and repeat if high
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Cryptococcal meningitis treatment
Well
Obtunded
Fluconazole 400mg bd
Amphotericin (renal marrow toxicity)
Fluconazole 400mg Maintenance HAART
5-Fluorocytosine may increase rate Of clearance
of cryptococcus
Maintenance until CD4gt100 / 6months
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Eye problems
Vitreous haemorrhage
CMV (CD4 lt50/mm3)
Retinal detachment
Toxoplasma
Infections (TB, PCP)
Rarities
Tumours
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CMV retinitis treatment

• HAAART
• and
• Ganciclovir
• Valganciclovir
• Cidofovir

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Constitutional symptoms
Fever Weight Loss
Lymph nodes
Look everywhere
Mouth
Skin
Differential diagnosis Sepsis TB MAI (CD4
lt50/mm3) Lymphoma (LDH, CT if available)
Eyes
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MAI

• Anaemia
• Weight loss
• Fever
• Abdominal pain / hepatomegally
• CD4 lt50/mm3
• Raised Alk Phos

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MAI treatment

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

Resistance develops rapidly
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HIV wasting

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

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When to start HAART-ACTG A5164 Immediate vs
Deferred ART in Patients With Acute OIs
Stratified by CD4 cell count lt or ? 50
cells/mm3, PCP, BI, or other OI
Immediate Antiretroviral TherapyInitiation
within 48 hours of randomization and within 14
days of starting OI treatment (n 141)
HIV-infected patients receiving treatment for
presumed or confirmed acute OI/BI (N 282)
48 weeks
Deferred Antiretroviral TherapyInitiation
between Weeks 4 and 32 (n 141)
48 weeks
Patients with TB excluded.
Zolopa A, et al. CROI 2008. Abstract 142.
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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

100
80
60
P .035
Patients Progressing to AIDS or Death at Week 48
()
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24.1
20
14.2
0
Immediate
Deferred

• Week 48 virologic outcomes similar between groups
• Safety and incidence of IRIS similar between
  groups

Zolopa A, et al. CROI 2008. Abstract 142.
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TB and HIV
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Global TB Estimates (2006)

• Estimated Cases Estimated Deaths
• All Forms TB 8.8 million 1.6
  Million
• MDRTB 424,000 116,000
• XDR-TB 27,000 16,000

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TB

• More dissemination
• Less cavitation
• More blood culture positive
• Not every abnormal CXR is TB, treat for bacterial
  pneumonia first

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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

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Inability of the PPD in distinguishing active TB
from inactive infection
TB contacts
Active TB
Latent TB infection
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Distribution of induration sizes of the
tuberculin (10 IU) skin test healthy young
students in France
n 435
60
50
40
Number of subjects
30
20
10
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Induration size of the tuberculin skin test (mm)
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Distribution of induration sizes of tuberculin
(10IU) skin test in HIV TB subjects in France
n 49
25
20
15
Number of subjects
10
5
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Induration size (mm)
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Abandon PPD?

• In HIV patients.. In developing world
• Screen for active tb with history and chest Xray
• give all rest Isoniazid
  chemoprophylaxis
• Dont screen but give all asymptomatic patients
  Isoniazid chemoprophylaxis
• In developed world
• Give INH until CD4 is over 200

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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

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T-SPOT.TB performance in HIV-1 patients is
comparable to that reported in immune competent
patients
Am J Resp Crit Care Med 2006 174736-742
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No correlation between CD4 T cell count and
magnitude of TB antigen responses
2500
2000
1500
No. TB antigen specific T cells / 106 PBMCs
1000
500
0
800
600
400
200
0
CD4 T cell count (cells/ul)
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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

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TB prevention-use HAART!

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

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INH for TB/HIVTuberculin skin test positive
patients
Tuberculin skin test positive patients
Favours isoniazid
Favours control
study
1 2 4 5
3
All Studies
0.05 .1 .2 .3 .4 .5 1
2 3 4 5 10 20
Risk ratio 95 CI
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Isoniazid (INH) for TB/HIVTuberculin skin test
negative patients
Favours isoniazid
Favours control
Tuberculin skin test negative patients
study
1 2 3 5
4
All Studies
0.05 .1 .2 .3 .4 .5 1
2 3 4 5 10
Risk ratio 95 CI
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Proportion of Individuals Dropping Out of
Preventative Therapy (PT) in Feasibility Studies
HIV persons entering the PT process ()
Those entering the process who started PT ()
HIV seroprevalence in study population ()
1995 Uganda 1995 Rwanda 1995 Zambia 1997 Thai
land 1998 Uganda 1999 Brazil
23 53 47 100 100 100
15 95 34 100 51 100
30 12 38 89 38 75
62 - - 69 70 61
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Impact of HAART on Incidence of TB in
HIV-Infected Adults

• Adults
• Initial reduction in TB incidence 11 to 3
• Incidence remained low over 5 years but still 1
  per annum on HAART

TB Incidence During HAART
5.5
4.5
P trend .02
3.5
TB Incidence Rate (Cases/100 PYs)
2.5
1.5
0.5
-0.5
1
2
3
4
5
Years of HAART
Lawn S, et al. CROI 2006. Abstract 68.
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Effect of CD4 count on risk of TBamong
HIV-infected people
Incidence of TB (per 100 pyrs)
20
gt350
200-350
lt200
15
10
5
0
Italy
US
South Africa
Antonucci JAMA 1995274143 Markowitz Ann Int
Med 1997126123 Badri Lancet 20023592059
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Issues in initiating antiretroviral therapy in
HIV patients with TB
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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

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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

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Rifampicin

• The major problem is the use of rifampicin with
  HAART
• But at present it is an essential part of the
  solution for TB

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CYP3A4 Regulation

• PXR pregnane X receptor RXR retinoid X
  receptor
• In vitro models now exist for identifying
  drugs that bind PXR

Wilson. PXR, CAR, and drug metabolism. Nat Rev
Drug Disc 2002
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Drug-drug interactions TB/HIV
Absorption
Rifampicin ?CYP3A4
Metabolism
PIs NNRTIs
Metabolism
Elimination
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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 effect
• Enfurvitide
• - No effect

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Rifampin NVP standard dose case series from
HIVNAT pK Lab (n60)
85 of NVP levels in therapeutic range
David Burger 2005 BKK Symp HIV Med, data
provided by Saskia Autar
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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
Arm 1 NVP 400 mg/day ( GPOvir Z 1 tab po
BID) Lead in 14 days with NVP 200 QD
N32, ARV naïve, TB/HIV, smear pos, CD4lt200,
RIF 2-6 weeks
Arm 2 NVP 600 mg/day ( GPOvir Z 1 tab po BID
NVP 1tab QD) Lead in 14 days with NVP 200 BID
All patients received AZT3TC as a backbone
24weeks interim analysis
48 weeks
2-6 weeks of TB treatment
14 days
12 weeks
2 weeks
4 weeks
Assessments



TDM of NVP

12 hr of NVP
Prospective, randomized, multicenter, open-label,
2-arm study
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Proportion of c-min NVP lt 3.1 mg/L

plt0.05
patients
Week 2
Week 4 Week
12 N 14 16
13 11 12
10 P-value 0.002
0.596
0.323
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Summary of adverse events


disseminated MAC, bloody pleural
effusion and liver mass
cardiomyopathy and heart failure
Table 4. Summary of adverse events
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Efavirenz

• PK data
• Standard dose?
• Increased dose?

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

• EFV dose 30 increase (from 600 to 800) adequate
• Body weight important determinant on CL

Soy et al. 2005
PK of EFV 800 mg plus rifampicin similar to those
of EFV 600 mg without rifampicin
Lopez-Cortes et al. 2002
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EFV levels in HIV-infected Thai patients with TB
600mg
800mg
Manisuthi et al. 2005
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Nevirapine and Efavirenz

• What is also important is
• Clinical outcome
• Toxicity

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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 lt400 copies
  compared with those on EFV or not on TB RX

Bollue 38th World Lung Health Conference 2007
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Boosted PIs and Rifampin Interaction
Lopinavir/rit
Saquinavir/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

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

1La Porte, AAC, 2004Berger pkw2007
2Roche Dear Doctor, 2005
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TB Treatment RegimensRIFAMPICIN / HAART
HAART Dose TB
Dose therapy 4NRTI No change
RIF No change nevirapine 200 mg bd RIF 600
mg od nevirapine 300 mg bd? RIF 600 mg
od efavirenz 6-800 mg od RIF 600 mg od
Dose adjusted?
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Rifabutin

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

CYP3A4
CYP3A4
Rifabutin
Active metabolites (i.e. 25-O-desacetyl,
31-hydroxy)

• CYP3A4 inhibitors increase rifabutin levels

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What about Rifabutin?
Benefits
Limitations

• 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

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TB Treatment RegimensRifabutin
HAART Dose TB
Dose therapy 4NRTI No change
RBT No change Boosted PI No change RBT
150? mg 2-3/7 nevirapine 200 mg bd RBT 300 mg
od efavirenz 600 mg od RBT 450 mg od
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Newer HIV drugs
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When to Start ART in TB Immediately?
TB TREATMENT
1
2
6
TB, HIV CD4lt350 Or ?lt200
Months
ANTIRETROVIRAL THERAPY-WHEN?
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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

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Dont Wait till its too lateFurther AIDS

• 27/188 TB/HIV patients developed further AIDS
• On HAART 3
• Not on HAART 24
• median CD4 70 cells
• 90 had median CD4 lt100 4 months post TB
• 16 died only 4 on HAART (3 short term)

Dean et al AIDS 2001
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Mortality among patients with prevalent active TB
(n73) initiating ART
a)
No difference in CD4 count or Stage 4 disease
between those starting and not starting
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HIV/TB

• What is IRIS?
• How is it diagnosed?
• How is it managed?

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(No Transcript)
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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

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HIV/TB

•  
• Presenting features of IRIS n
• Lymphadenopathy 12
• Fever 8
• Sternal skin lesion 2
• Spleen micro abscesses 1
• Gluteal abscess 1

Michaelidis AVT 2005
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HIV/TB

• Factor IRIS Non-IRIS p
• N 14 41
• Baseline CD4 (cells/mm3) 80 (33 117) 139 (77
  284 )0.050
• Baseline CD4 lt 100 11 (78.6) 16 (39.0) 0.011
• Baseline 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 0.046
• from baseline to 3 months (0.6 to 5.6)
  (-0.2 to 1.0)

Michaelidis AVT 2005
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Cytokine gene SNP alleles are associated with
immune restoration diseases
IL-6 -174C
TNFA-3082
IL-12-3UTR2
IL-12-promoter2
plt0.05 (Compared with non-HIV controls)



Non-HIV (N gt100)
HIV, Non-IRD (N 33)
Herpesvirus (N 25)
Mycobacterial (N 11)
HCV (N 13)
Price P et al, AIDS 2002,162043
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Management of immune restoration disease

• Suppression of inflammatory response by
  corticosteroid therapy
• Treatment (DTH gt 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

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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 wont differentiate from
  latent TB

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Definition of XDR-TB

• MDR-TB Resistance to at least Rifampicin and
  Isoniazid
• XDR-TB MDR-TB plus resistance to
• a fluoroquinolone and
• gt1 of 3 injectable second-line drugs capreomycin,
  kanamycin, amikacin
• (New definition agreed October 2006)
• Causes
• Poor treatment
• Lack of resistance surveillance
• Infection control

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Countries with confirmed XDR-TB
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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.