TB

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TB HIV Whats New in Tuberculosis
David Ashkin M.D. Florida State TB
Controller Medical Executive Director, A.G.
Holley State TB Hospital Co-PI, Southeast
National TB Center Clinical Associate Professor,
Department of Pulmonary and Critical Care,
University of Miami, School of Medicine
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• The Lord shall smite thee with a consumption and
  with a fever, and with an inflammationand they
  shall pursue thee until thou perish.

Deuteronomy 2822
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TB Case Rates, United States, 2004
D.C.
lt 3.5 (year 2000 target)
3.64.9
gt 4.9 (national average)
Cases per 100,000.
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Factors Contributing to the Increase in TB
Morbidity

• HIV epidemic
• Increased immigration from high-prevalence
  counties
• Transmission of TB in congregate settings
• Deterioration of the health care infrastructure

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TUBERCULOSIS

• GLOBAL USA
• Infected Cases 1.7 Billion 10 million
• (33 Population) (4 Population)
• Case Incidence 8-10 Million/yr 18,000/yr
• Case Prevalence 40-50 Million 30 thousand
• Deaths 1.8 Million/yr 1,000-2,000/yr
• MDR Up to 15 lt1
• (DR and Equador)

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TB and HIV at the Turn of the 21st Century

• TB kills more people worldwide than ever before
• -2-3 million people die every year
• -Leading cause of death among HIV infected
  individuals
• -AIDS kills 8000 people a day, of which 5000 die
  of TB
• -one every 10 seconds
• -If TB is left unchecked in the next 20 years,
  almost 1 billion people newly infected and 200
  million will develop disease and 35 million will
  die
• TB HIV kill more individuals than any other
  infectious diseases
• -Most are 25-44 year old individuals (Leading
  curable infectious killer among young adults)
• Leads to loss of work force
• Leads to orphans
• -9 million children are orphaned in Africa

The Deadly Partnership
TB
HIV
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Transmission Of Tuberculosis
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Pathogenesis of Tuberculosis
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Disease Progression

• Progression from infection to disease caused by
  an inability to contain infection
• 5-10 of all HIV(-) will progress from infection
  to disease
• Up to 8 per year of PPD(), HIV() pts will
  progress from infection to disease
• The average patient with active TB infects 30
  other individuals

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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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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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Diagnosis Of Active TB Disease

• Key
• THINK TB

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Infection Control

• THINK TB, ISOLATE START MEDS
• 6-8 air exchanges/hr
• Negative Pressure
• Doors Closed
• All entering room wear N95 mask
• Keep in isolation until 3 negative smears, on
  medications and responding clinically

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DIAGNOSIS OF TB DISEASE

• Chest X-Ray
• 95 of HIV(-) cases with upper lobe infiltrates
  and/or cavities

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DIAGNOSIS OF TB DISEASE

• Up to 30 of HIV (), active TB cases will have
  no infiltrates or cavities

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TB Disease Diagnosis

• Smear
• Cheap rapid
• Only 40-60 positive in cases of active TB

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TB Disease Diagnosis

• Culture
• Positive 80 of active TB cases
• Takes 6-8 weeks by conventional
• Takes 1-3 weeks by liquid media
• Sensitivity
• Takes 1-2 weeks after positive culture
• Nucleic Acid Amplification
• Results available in 4-6 hours
• Specificity 98 on smear() specimens
• Sensitivity 70-80 on multiple respiratory
  specimens

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General Principles of Chemotherapy for TB Disease

• 1) Existence of mutant bacilli with innate
  resistance to antibiotic action

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DEVELOPMENT OF RESISTANCE
INH
I
I
I
I
I
INH
I
I
INH
RIF
RIF
I
INH
INH
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• MORE BUGS-MORE DRUGS!!!!!
• J. Sbabaro

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General Principles of Chemotherapy for TB Disease

• 1) Existence of mutant bacilli with innate
  resistance to antibiotic action
• 2)Slow or intermittent growth of mycobacterium
  which permits the persistence of viable organisms
  despite prolonged antibiotic treatment, because
  only actively replicating organisms are killed by
  antibiotics

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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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Rifamycin Mono-resistance and HIV

• CDC Rbt/ARV and other studies have shown that Rbt
  is highly effective at curing TB in HIV infected
  patients with 95 efficacy but 4 (all with
  CD4lt100) on BIW therapy relapsed with rifampin
  monoresistance
• Suggested that long half life of Rbt combined
  with short half life of INH left Rbt unprotected
• However other studies suggested this happened
  with rifampin also which has shorter half life
• Malabsorption of TB drugs seen in those who
  developed monoresistance
• Our study suggested also presence of
  extrapulmonary disease
• ? More Bugs in these sites in HIV with low CD4
  with selected penetration
• Recommend TIW treatment

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TREATMENT OF ACTIVE TB DISEASE

• Start with 4 drugs in all patients
• INH, RIF (RBT), PZA and EMB or SM until
  sensitivities return
• If pansensitive, D/C EMB or SM
• After 2 months of therapy, D/C PZA
• Continue INH RIF(RBT) for 4 more mths-total 6
  mths
• Must have culture conversion by 2 months
• 6 month regimen good for HIV(-) and ()
• Can use BIW regimen if CD4gt100 (? RIF
  Monoresistance in HIV pts with CD4lt100 use TIW)
• Monitor adherence and toxicity
• DOT preferred, Combination pills for self
  administered

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ATS/CDC/IDSA Treatment Guidelines 2003

• Responsibility for successful treatment is
  clearly assigned to the public health departments
• Strong recommendations for initial patient
  centered case management and DOT
• Recommend getting sputum cultures at 2 months to
  identify potential relapse
• Extended treatment for those still with positive
  cultures at 2 months and cavities on CXR
• Role for rifabutin, rifapentine and
  fluoroquinolones
• Treatment completion defined by number of doses
• as well as duration of therapy

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DOT THERAPY WORKS!

• 95 of patients with TB will be cured by DOT
• Decreases Morbidity Mortality and cost
  (1500/pt)
• Decreases Spread of Disease
• Average patient with TB infects 30 other
  individuals
• Decreases resistance
• MDR costs250,000 to cure with only 80 success
  
• 5 of patients with Active TB will be unable to
  complete therapy requiring legal interventions
  and facilities to cure them
• In S.F. one non-compliant patient with MDR-TB was
  responsible for 40 other cases

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Clinical Significance of Resistance

• If pansensitivegt95 chance of cure
• If resistant to INHgt90 chance of cure
• If resistant to rifampingt70 chance of cure
• If resistant to INH and RIF50 chance of cure
• Before chemotherapy50 chance of cure

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• Increased MDR resistance among HIV
• ? Increased transmission in NY due to poor TB
  Control Efforts in early phases of epidemic
• More chance for congregate settings with
  individuals who may have MDR (e.g. hospitals,
  clinics or hospices)
• ? More organisms with impaired absorption or
  altered metabolism

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TB Treatment Monitoring

• Observe for response-weight gain, coughing less,
  improved appetite, decreased fevers, AFB smears
  decreasing
• Repeat cultures at two months
• Observe for drug toxicities
• INH
• hepatitis with transaminase elevation-monitor for
  clinical signs of hepatitis and at least monthly
  LFTs
• Peripheral neuropathy-monitor clinically, give B6
• Rifampin
• Red color to urine, sweat, tears
• Myalgias-NSAIDS prn
• Cholestatic hepatitis-monitor for clinical signs
  of hepatitis and at least monthly LFTs
• Pancytopenia-CBC monthly
• Rifabutin-same as rifampin except uveitis more
  common
• Ethambutol
• GI upset-? Metoclopramide (try not to give TB
  meds with food)
• optic neuritis (esp in pts with decreased renal
  function)-monitor clinically, monthly color
  vision and visually acuity
• Pyrazinamide
• hepatitis with transaminase elevation-monitor for
  clinical signs of hepatitis and at least monthly
  LFTs
• Increased uric acid (gout)-monitor clinically and
  if symptomatic and elevated uric acid-allupurinol
  
• CXRs not routinely recommended for f/u

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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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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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How Can we Prevent TB among HIV patients?

• Detect HIV early (Strongest determinant for
  patients progressing from infection to disease)
• Test all patients who are HIV () annually with
  PPD test (gt5mm) (Risk of progressing from
  infection to disease in HIV infected patients is
  8-10/year as opposed to 5-10/lifetime in HIV(-)
  )
• 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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Diagnosis of TB InfectionTuberculin Test
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Whole Blood Gamma Interferon Assay for LTBI

• Quantiferon recently approved by FDA
• May be able to discern reaction to BCG and NTM
• More studies needed to discern role in LTBI
  diagnosis

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How Can we Prevent TB among HIV patients?

• 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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Treatment of Latent Tuberculosis Infection
(Formerly Known as Preventive Therapy)

• Treatment of latent TB infection
• for HIV(), 9 mo INH (instead of 12 mo)
• Short Course Treatment of LTBI no longer
  routinely recommended
• RIF for 4 months as effective as INH for 9 months

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WHAT CAN YOU DO TO COMBAT TUBERCULOSIS

• CONTACT LOCAL HEALTH DEPARTMENT TO HELP ARRANGE A
  PLAN OF THERAPY FOR PATIENT-HEALTH DEPARTMENTS
  ARE RESPONSIBLE FOR THE CURE OF TUBERCULOSIS
  PATIENTS
• BEGIN 4 MEDICATIONS ON ALL PATIENTS UNTIL
  SENSITIVITY OF ORGANISMS RETURNS
• EDUCATE PATIENT ABOUT TUBERCULOSIS AND IMPORTANCE
  OF ADHERENCE TO MEDICATIONS
• CONSIDER HAVING PATIENT SIGN ACKNOWLEDGEMENT FORM
• MONITOR FOR EFFECTIVENESS OF THERAPY, ADHERENCE
  AND SIDE EFFECTS
• CONSIDER DOT THERAPY
• IF DOT THERAPY FAILS CONSIDER COURT ORDERED DOT
• INVOLUNTARY COMMITMENT

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A.G. HOLLEY TB HOTLINE
1-800-4TB-INF0