HIV

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HIV Tuberculosis 2008

• David Ashkin M.D., FCCP
• Medical Executive Director, A.G. Holley State TB
  Hospital
• State TB Health Officer, Florida Department of
  Health
• Medical Director/Co-PI Southeast National TB
  Center
• Clinical Assistant Professor, Dept of Medicine,
  UF School of Medicine
• Voluntary Associate Professor, Division of
  Pulmonary and Critical Care Medicine, University
  of Miami School of Medicine
• Faculty, Fogarty International Training Program
  in HIV/AIDS TB

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Disclosure of Financial Relationships

• This speaker has no significant financial
  relationships with commercial entities to
  disclose.

This slide set has been peer-reviewed to ensure
that there areno conflicts of interest
represented in the presentation.
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The Lord shall smite thee with a consumption and
with a fever, and with an inflammation . . .and
they shall pursue theeuntil thou perish.

• Deuteronomy 2822

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TUBERCULOSIS

• GLOBAL USA
• Infected Cases 1.7 Billion 10 million
• (33 Population) (4 Population)
• Case Incidence 8-10 Million/yr 15,000/yr
• Case Prevalence 40-50 Million 25 thousand
• Deaths 1.8 Million/yr 1,000-2,000/yr
• MDR Up to 15 lt1
• (DR and Ecuador)

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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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TB and HIV Today
The Deadly Partnership
TB
HIV
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TB and HIV Today

• 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

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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
Severely Immunosuppressed HIV ()
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)
• 14 percent of patients with HIV-TB died within 6
  months of TB diagnosis, in contrast to 0.5
  percent of patients with TB alone.
• (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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Diagnosis of Active TB Disease

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

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Diagnosis of Active TB Disease

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

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Extra-pulmonary TB

• 10 in HIV(-)
• HIV()
• 33 with extrapulmonary alone
• 33 with pulmonary alone
• 33 both pulmonary and extrapulmonary (many with
  negative CXRs)
• Any organ has been noted to be involved
• Pleural dx most common
• Lymph nodes
• GU
• Bone (Need to prolong therapy)
• Abdominal
• CNS (Need to prolong therapy)

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TB Disease Diagnosis

• Smear
• Cheap rapid
• Only 40-60 positive in cases of active TB
• The Standard for Diagnosis of TB in most of the
  world

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TB Diagnosis

• Culture
• Takes 6-8 weeks by conventional
• Takes 1-3 weeks by liquid media
• Need 100 organisms/ml to get 1 colony
• Sensitivity-Positive in 80 of CDC Verified Cases
• Specificity- 1-2 False Positive
• Susceptibility
• Takes 1-2 weeks after positive culture
• Molecular Techniques have the ability to give
  more rapid results
• Most of the World Does Not Have Access to these
  critical laboratory tests!!!

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TB DiagnosisNucleic Acid Amplification
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TB DiagnosisNucleic Acid Amplification

• Results within 8 hours 99 specificity on smear
  () cases
• Up to 80 sensitivity on 3 samples
• 30-50/test
• Approved by the FDA for smear positive
  negative, untreated cases
• May have a role in non pulmonary samples

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General Principles of Chemotherapy

• Existence of mutant bacilli with innate
  resistance to antibiotic action

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DEVELOPMENT OF RESISTANCE
INH
I
I
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I
I
INH
I
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INH
RIF
RIF
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INH
INH
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General Principles of Chemotherapy

• Existence of mutant bacilli with innate
  resistance to antibiotic action
• 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 Disease

• Start with 4 drugs in all patients
• INH, RIF, 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 for 4 more months for total of
  6 months
• Must have culture conversion by 2 months
• 6 month regimen good for HIV(-) and ()
• Can use BIW regimen (TIW ? RIF Monoresistance in
  HIV pts after daily for first 2 months )
• Monitor adherence and toxicity
• DOT preferred, Combination pills for self
  administered

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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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Causes of Inadequate Response to Therapy

• Non Adherence!!!!!!!!!!!!!!!!!
• DOT
• Involuntary Detention
• Increased Drug Resistance/Incorrect Sensitivities
• Malabsorption/Increased Metabolism
• Inability of Drugs to Penetrate Effected Tissues

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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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Causes of Resistance

• Care of patients by non-specialists choice of
  drugs, dosages
• Program factors intermittent drug supply, lack
  of training, no DOT, lack of adequate laboratory
  support (eg lack of cultures and
  susceptibilities)
• Patient factors Irregular self administration,
  side-effects, malabsorption, inability to
  penetrate into areas of disease,
  misunderstanding, substance abuse, pregnancy,
  mental illness and poverty

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Financial Costs of MDR

• Cost 1500 to cure pansensitive patient by DOT
• Cost 250,000 to cure an MDR patient
• The average TB patient spreads their disease to
  30 other patients

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Extensively Drug Resistant TB (XDR)

• In 9/06 54 patients with HIV and TB in South
  Africa were described with XDR TB-52 of 54 Died
• In 11/06 XDR was redefined as the occurrence of
  TB in persons whose M. tuberculosis isolates are
  resistant to isoniazid and rifampin plus
  resistant to any fluoroquinolone and at least one
  of three injectable second-line drugs
  (i.e.,amikacin, kanamycin, or capreomycin)-These
  strains deemed virtually untreatable in most of
  the world.
• 2/08 WHO reported highest rates of resistant
  strains ever with 5 of new cases MDR with up to
  20 of new cases in certain areas (eg Former
  USSR)-10 of MDR cases are XDR

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XDR TB

• Since the original report many other countries
  including the US has reported cases of XDR TB
• XDR is harder to treat because
• Need more medications to treat
• Medications tend to be more toxic
• Many medications need to be given intravenously
• Need more expertise to administer the medications
• Needs more monitoring
• Much more expensive!!!
• Selection of the Fittest
• Since in most of the world XDR is not treatable,
  those with XDR remain contagious longer and thus
  potentially spread their disease to more
  individuals

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HIV Associated TB

• HIV-associated tuberculosis is more lethal than
  the TB seen in HIV-negative individuals.
• 14 percent of patients with HIV-TB died within 6
  months of TB diagnosis, in contrast to 0.5
  percent of patients with TB alone.
• In order to ensure the best outcomes for
  co-infected patients, clinicians should
  prioritize the appropriate treatment of
  tuberculosis, the highest level of adherence with
  TB therapy (ideally via DOTS), and the use of
  antiretroviral treatment (ART) in eligible
  patients.

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Adapted from WHO TB Care with HIV/TB
Co-Management 4/2007
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Rifabutin- (cont.)
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ART and TB

• Most recommend starting with NNRTIs (EFZ and NVP)
  and NRTIs due to less interactions
• Otherwise use PIs and NRTIs with dosage
  adjustments and ?RBT
• ? Start after 2 months of TB therapy
  (controversial)

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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
  (Inflammatory Response with Immune
  Reconstitution) may frequently be seen ( 11-45
  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-other possibilities for worsening must
  first be excluded

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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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Diagnosis of TB InfectionTuberculin Test
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Potential Skin Test Problems

• False Negative
• Critically ill TB patient
• Immunosuppressed person
• Recently vaccinated with live virus
• Recent TB infection
• False Positive
• Infected with Mycobacteria other than TB, e.g,
  MAC

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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
• May have a role in HIV infected individuals with
  CD4 countsgt100 cells
• More studies needed to discern role in LTBI
  diagnosis

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How Can We Prevent TBAmong 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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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 INHfor 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