David Ashkin M'D' F'C'C'P'

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TB
HIV
"MAKING SENSE OF IT ALL"
David Ashkin M.D. F.C.C.P. FL TB Controller,
Florida Bureau of TB and Refugee Health Medical
Executive Director, A.G. Holley State TB
Hospital Clinical Assistant Professor, Dept of
Medicine, UF School of Medicine
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G.D.

• 1st AGH admission for this 41 yo Hispanic male
  who was court ordered from Osceola County for non
  adherence on 6/12/03
• History is significant for early in 2002, the
  patient developed intense abdominal pain,
  dizziness, decreased appetite, fever, night
  sweats, purulent sputum, shortness of breath and
  a 40 pound weight loss over the previous 2 weeks.

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G.D.

• He was admitted to a hospital in New York and
  found to have an intestinal obstruction. The
  patient underwent a laparotomy, a cholecystectomy
  and an abdominal lymph node was found to be
  positive for TB.
• The patient was also found to be infected with
  HIV.

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G.D.

• A CXR and CT of the Chest was significant for
  paratracheal adenopathy. A mediastinal LN
  biopsy also grew TB.

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Which of the following statements is false?

• Up to 67 of HIV patients with TB have evidence
  of extrapulmonary disease.
• HIV patients with extrapulmonary disease have
  fewer TB organisms in their lesions.
• Miliary TB is more commonly seen in patients with
  HIV.
• Patients with TB in general have higher HIV
  viral loads
• Patients with HIV and TB who are cured of TB but
  untreated for HIV have a 20-35 one-year
  mortality rate.

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Which of the following statements is false?

• Up to 67 of HIV patients with TB have evidence
  of extrapulmonary disease.
• HIV patients with extrapulmonary disease have
  fewer TB organisms in their lesions.
• Miliary TB is more commonly seen in patients with
  HIV.
• Patients with TB in general have higher HIV
  viral loads
• Patients with HIV and TB who are cured of TB but
  untreated for HIV have a 20-35 one-year
  mortality rate.

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HIV makes TB worse

• Without T cells get immature response
• Host response can no longer contain TB organisms
  that may be present
• Taken to Lymph Nodes causing adenopathy and
  dissemination
• Greater chance of rapid progression from
  infection to disease with recent infection (? If
  greater chance of acquisition e.g. loss of innate
  resistance)
• May lose innate resistance so have the ability to
  get re-infected if exposed again
• Recent infection with post primary TB more common
  in HIV infected patients as shown in Genotyping
  studies from NY and SF
• Changes way TB presents-lower lobe, hilar
  adenopathy, pleural TB, extrapulmonary
  disseminated disease
• With severe immunosuppression may get no response
• CT and CXR negative

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Systemic Miliary TB
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TB in HIV
Poorly Formed to No Significant Granuloma
Formation in Severely Immunosuppressed HIV ()
Compared to well Formed Granulomas in HIV (-)
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Tuberculous Granuloma
HIV (-)
Severely Immunosuppressed HIV ()
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Copathogenicity of TB and HIV

• (1) TB causes T cells to release IFN-gamma
  activated macrophages by TB release TNF and IL-1
  those enhance HIV viral replication (--gtTB
  accelerates HIV)
• (2) one-year mortality rate for treated
  HIV-related TB 20-35 (!! 4 times higher than
  HIV(-) !!)

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Which Therapeutic Regimen would you start this
patient on at this time?

• INH/RIF/PZA
• INH/RIF
• INH/Rifabutin (RBT)/Ethambutol (EMB)/PZA
• INH/RIF/EMB/PZA/Kaletra/Combivir
• INH/RBT/EMB/PZA/Sustiva/Combivir

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Which Therapeutic Regimen would you start this
patient on at this time?

• INH/RIF/PZA
• INH/RIF
• INH/Rifabutin (RBT)/Ethambutol (EMB)/PZA
• INH/RIF/EMB/PZA/Kaletra/Combivir
• INH/RBT/EMB/PZA/Sustiva/Combivir

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G.D.

• The susceptibilities subsequently revealed
  resistance to INH0.1 and rifampin.

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G.D.

• The patient in 2002 was started on TB medications
  (? which meds and for how long) but was lost to
  follow up.
• Subsequently, the patient drove long distance
  trucks around the US (all 48 states) without
  any treatment for TB or HIV.

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G.D.

• The patient moved to Florida late 2002, but after
  an initial visit to the local health department
  was again lost to follow up.
• He subsequently resurfaced, but only received 10
  doses of medications by DOT he reportedly had a
  great deal of mental confusion. Due to the
  non-adherence to treatment, the patient was court
  ordered to AGH

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Admission CXRs
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G.D.

• Upon admission to AGH on 6/12/03, the patient was
  noted to have a left hemiparesis. An MRI of the
  brain that night showed multiple ring-enhancing
  lesions with a large amount of angiogenic edema
  in both the right basal ganglion and the right
  frontal/parietal lobe.

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Ring Enhancing Lesion in Basal Ganglia
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Ring enhancing lesion with massive edema
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Compression of Right Ventricle
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G.D.

• The patient was started on steroids, CNS MDR-TB
  therapy (INH 900 TIW, Levofloxacin 750mg qD, EMB
  1200mg qD, Rbt 300mg qD, PZA 1500mg qD, CS 250mg
  qD, CAP 750mg TIW IV, Vit B6 200mg qD) and
  anti-toxoplasmosis meds, in addition to
  Acyclovir.

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G.D.

• The patient clinically demonstrated an immediate
  response to the steroids with resolving
  hemiparesis.
• A repeat MRI of the Brain done 2 weeks later
  showed significant improvement in the angiogenic
  edema and mass effect but only a slight decrease
  in size of the lesions themselves the antitoxo
  meds were d/cd and the MDR-TB treatment
  continued.

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G.D.

• The patients VL on admission on 6/12/03 was
  6.3x105 with a CD4 count of 14 cells/mm3, 3.5,
  0.05.

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Would you start ARV now?

• Yes
• No

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• The patients VL on admission on 6/12/03 was
  6.3x105 with a CD4 count of 14 cells/mm3, 3.5,
  0.05.
• Given the severe immunosuppression, after
  discussion (including the possibility of
  developing Immune Reconstitution Inflammatory
  Syndrome-IRIS), a decision to start ARV was made
  (RBT switched to TIW, EFZ 600mg qD, Combivir
  BID).
• The patients VL at the time of starting ARV on
  8/7/03 was 1.5x105 with a CD4 count of 13
  cells/mm3, 1, 0.01.

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When To Start ARV Therapy?

• Considerations
• - Viral load
• VLlt30,000 copies associated with slow progression
• - CD4
• - symptoms
• - PATIENT

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LIFE EXPECTANCY

• VL AIDS IN 6 Y DEATH IN 6 Y
• lt 500 5.4
  0.9
• 501 3000 16.6 6.3
• 3000 10,000 31.7 18.1
  
• 10,000-30,000 55.2 34.9
• gt 30,000 80.0
  69.5

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Treatment of active TB in Patients on
Antiretroviral Therapy

• Rifabutin (RBT-T1/245 hours) preferred over
  rifampin (Rif-T1/25 hours) due to less p450
  interactions
• Must adjust dosages of ARV and RBT if given
  concurrently
• INH/RBT/PZA/EMB daily for 2 wk (? 2 mth), then
  tiw for 6 wk (don't drop EMB) then INH/RBT for 4
  more mo (RBT toxicity arthalgia, uveitis,
  leukopenia) (monitor viral load)
• Alternative regimens is not to use a rifamycin or
  delay ARV therapy

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If CD4 count is greater than 100 cells/mm3, may
consider BIW administration of RBT with APV,
fos-APV, IDV, NFV, EFZ and NVP
Adapted from MMWR 1/23/04
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G.D.

• Patient responding clinically including improved
  neurological function
• However, upon attempts to taper his steroids, he
  again became increasing confused.
• A repeat MRI on 9/5/03 showed improved old
  lesions but new foci with vasogenic edema in the
  right basal ganglia and hypothalmus.

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Old Lesions Better
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What is happening in his Brain?

• New Toxoplasmosis
• Cystercercosis
• Lymphoma
• Immune Reconstitution
• Cryptococcoma

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What is happening in his Brain?
?
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G.D.

• At the time of the appearance of the new lesions,
  on 9/12, the patients VL was 6x102 and his CD4
  was 39 cells/mm3, 6 0.09 (Previously 8/7/03
  1.5X105, CD4 13, 1, 0.01)
• Due to the new lesions and associated neurologic
  deterioration, the steroids were once again
  increased with subsequent clinical improvement.

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Paradoxical Responses
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Paradoxical Response

• Soon after ARVs are started (2-6 weeks) in
  patients with HIV and TB, paradoxical responses
  (Immune Reconstitution with Inflammatory Response
  Syndrome-IRIS) may frequently be seen ( 25 esp.
  in patients with an initially high HIV viral load
  who experience a marked drop post ARVs)
• These paradoxical responses frequently arouse
  concerns of uncontrolled TB due to drug
  resistance and/or noncompliance, drug fever or
  alternative diagnosis, they are distinct from
  these and may represent an enhanced
  antituberculous immune response after the
  initiation of anti-retroviral therapy
• Clinicians should be aware of this phenomenon
  although other possibilities for a worsening
  clinical state must first be excluded
• Potentially many will regain their ability to
  react to PPD

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G.D.

• Again attempts made to taper steroids.
• On 9/24/03, the patient began complaining of
  right eye pain and decreased vision.
• The patient was seen by the ophthalmologist who
  found evidence of extensive right optic nerve
  involvement (pale disc) without papilledema. No
  evidence of CMV seen.
• Repeat Brain MRI that night revealed a
  significant increase in the right basal ganglia
  and hypothalmus lesions now compressing the optic
  tract

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What would you do now?

• Biopsy
• Treat with Trimethoprim/Sulfadiazine
• Add Mebendazole
• Radiation
• Amphotericin

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What would you do now?

• Biopsy
• Treat with Trimethoprim/Sulfadiazine
• Add Mebendazole
• Radiation
• Amphotericin

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G.D.

• The steroids were again increased and antitoxo
  meds re-begun
• Arrangements for a brain biopsy was initiated.
• The patient started developing pancytopenia with
  a WBC 1.9, Hct 19, plt 61k. This was thought
  secondary to the sulfadiazine (despite
  leukovorin) which was d/cd and clindamycin
  begun. Patient required transfusions, Epo and
  GCSF begun. Biopsy held due to pancytopenia
• The patient started developing hyperglycemia
  thought secondary to the high dose steroids.
  Also the patient developed Cushinoid features
  clinically.

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G.D.

• A repeat MRI of the Brain performed 2 weeks after
  the steroids were increased revealed a
  significant decrease in the size of the lesions
  and edema
• The patient exhibited marked clinical improvement.

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G.D.

• The patient gained 55 pounds
• He was once again able to walk and had improved
  vision
• His TB was sputum smear and culture negative
  (Never had positive sputum cultures)
• Serum TB drug levels were within normal limits
• 9/22/03 VL lt400, 28cells/mm3, 4, 0.06

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G.D.

• In early 11/03 the patient was again noted to
  have had a worsening of his neurologic signs and
  symptoms including visual disturbances and left
  paresis while on Decadron 3mg q6o (?10mg q6o).
• Repeat MRI of the Brain on 11/3/03 revealed a new
  lesions in the left cerebellum, right posterior
  frontal lobe and left centrum ovale, with
  surrounding edema and mass effect of the right
  basal ganglia lesion.

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G.D.

• CXR now showed multiple nodules

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10/7/03
11/4/03
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What now?
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What would you do now?

• Biopsy
• Treat with Trimethoprim/Sulfadiazine
• Add Mebendazole
• Radiation
• Amphotericin

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What would you do now?

• Biopsy
• Treat with Trimethoprim/Sulfadiazine
• Add Mebendazole
• Radiation
• Amphotericin

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G.D.

• Liposomal Amphotericin was begun empirically
• Transthoracic biopsy of the lesion was obtained
• Biopsy was QNS, showing only mesothelial cells,
  multinucleated giant cells but cultures grow
  aspergillus
• Blood and sputum cultures for bacteria, viral and
  fungus were negative

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G.D.

• CXRs showed an improvement in the size of the
  lesions with further cavitations

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G.D.

• Repeat MRI of the Brain on 11/13/03 showed
  worsening of the lesions despite liposomal
  amphotericin. Vorconazole added
• Biopsy of the Brain arranged after consultation
  with the UM Neurosurgery Dept
• The patient deteriorated and became unstable with
  decreased mental status and hypotension
  preempting the biopsy
• Patient expired on 11/29/03

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PCP in Lungs (HE Stain)
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PCP Silver Stain
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Aspergillus in the Lung
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CMV in The Esophagus
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GD-Final Autopsy Report

• Disseminated aspergillosis involving lungs,
  kidneys, thyroid and CNS
• Fibrotic areas in frontal lobes of Brain,
  periventricular ? c/w TB scaring (AFB Cx (-))
• Disseminated CMV involving lungs, kidneys,
  adrenal glands and esophagus
• Pneumocystis carinii pneumonia

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How Could The TB Have Been Prevented?

• Detect HIV early
• Test all patients who are HIV () annually with
  PPD test
• Problems
• Anergic
• Routine Anergy Testing not recommended
• ? Treat those with TB risk factors presumptively
  for LTBI
• ? Treat with ARV and repeat PPD in 3 months

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How Could The TB Have Been Prevented?

• Assure that those with PPD () complete LTBI
  treatment!!!
• Assure that all HIV () with active TB are on DOT
  and complete therapy before the development of
  resistance and worsening of immune function!!

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Summary Management HIV/TB is complicated by

• Severe immunosuppression with worsening of both
  Dxs
• Increased incidence of extrapulmonary disease
  with uncertain drug penetration
• Need for numerous drugs with increased risk of
  adverse drug interactions and non adherence
• Complex drug interactions
• Immune reconstitution syndromes
• Concomitant medical conditions
• Increased risk of resistance

Try to prevent development of TB by detecting and
treating TB infection
Call an Expert!!!!
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