HIV AND TUBERCULOSIS: A SPARK THAT LIGHTS THE FIRE

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HIV AND TUBERCULOSIS A SPARK THAT LIGHTS THE
FIRE
David Ashkin M.D. State TB Health Officer Medical
Executive Director A.G. Holley State TB
Hospital Clinical Associate Professor, Department
of Pulmonary and Critical Care University of
Miami, School of Medicine Co-Principal
Investigator, Southeastern National TB Center
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OUTLINE

• TB Epidemiology
• TB Transmission
• TB-HIV Copathogenicity
• TB Diagnosis
• TB Treatment
• TB Treatment in HIV patients
• TB and HIV A Recipe for Resistance?
• LTBI

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OUTLINE

• TB Epidemiology
• TB Transmission
• TB-HIV Copathogenicity
• TB Diagnosis
• TB Treatment
• TB Treatment in HIV patients
• TB and HIV A Recipe for Resistance?
• LTBI

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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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Tuberculosis

• GLOBAL USA
• Infected Cases 1.7 Billion 10 million
• (33 Population) (4 Population)
• Case Incidence 8-10 Million/yr 13,000/yr
• Case Prevalence 40-50 Million 30 thousand
• Deaths 1.8 Million/yr 1,000-2,000/yr
• MDR Up to 15 1.2
• (DR and Equador)

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HIV-TB Dual Pandemics

• 15 of the new TB infections occur in HIV pts
• 1 out of 4 TB deaths is HIV related
• Annual incidence and mortality due to TB globally
  would be falling if it were not for HIV infection
• In some countries, 80 of TB patients are
  co-infected with HIV
• Autopsy studies have shown rates in excess of 33
  among people dying of AIDS

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TB at the Turn of the 21st Century
The Deadly Partnership
TB
HIV

• TB HIV kill more individuals than any other
  infectious diseases
• -Most are 25-44 year old individuals
• Leads to loss of work force
• Leads to orphans
• -9 million children are orphaned in Africa
• World Bank says an effective TB program is the
  most cost
• effective program for developing countries

8
TB Worldwide 2009

• TB kills more people worldwide than ever before
• -2-3 million people die every year
• -one every 10 seconds
• WHO reports TB Drug resistance is on the rise
• -China, India, and Russia account for more than
  half (57) of all global cases
• - 30,000 MDR-TB cases in 2007 8.5 of the
  estimated global total of smear positive cases
  only 1 of the MDR cases received tx in
  accordance with international guidelines
• -Other reports show in Equador and Dominican
  Republic 15
• -Countries that use DOT have lower rates of
  resistance

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We have to stop people living with HIV from
dying of tuberculosis

• Dr. Michael Sidibe, 2009
• Director of UNAIDS

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Reported TB Cases United States, 19822008
No. of Cases
Year
Updated as of April 23, 2008.
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TB Case Rates, United States, 2007
D.C.
lt 3.5 (year 2000 target)
3.64.4
Cases per 100,000.
gt 4.4 (national average)
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TB MorbidityUnited States, 20022007
Year No. Rate

• 2002 15,056 5.2
• 2003 14,837 5.1
• 2004 14,501 4.9
• 2005 14,065 4.7
• 13,754 4.6
• 13,299 4.4

Cases per 100,000, updated as of April 23,
2008.
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TB in US 2008

• TB rate in foreign born in US is 10x higher than
  US-born
• 4 states (California, NY, Florida and Texas)
  reported more than 500 cases each and combined
  they account for almost half (49.2) of all TB
  case in US
• 4 countries accounted for half of the foreign
  born cases Mexico, Philippines, India and
  Vietnam
• 81 of MDR cases occurred in the foreign-born

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Factors Contributing to the Increase in TB
Morbidity

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

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Tuberculosis Cases by HIV Test StatusFlorida,
2008
n161
Percentages have been rounded and may not equal
100
Provisional data from TIMS Indeterminate cases
were less than 1.
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OUTLINE

• TB Epidemiology
• TB Transmission
• TB-HIV Copathogenicity
• TB Diagnosis
• TB Treatment
• TB Treatment in HIV patients
• TB and HIV A Recipe for Resistance?
• LTBI

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Everyone knows the air is terribly infected from
the numerous mortals who have died exhaling it

• Moby Dick
• Herman Melville

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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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OUTLINE

• TB Epidemiology
• TB Transmission
• TB-HIV Copathogenicity
• TB Diagnosis
• TB Treatment
• TB Treatment in HIV patients
• TB and HIV A Recipe for Resistance?
• LTBI

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TB HIV Background

• The rate of TB disease among HIV(), PPD() was
  200-800 times higher than general population (HIV
  accelerates TB)
• The rate of TB disease among HIV(), PPD() was
  4-26 times higher than HIV(), PPD(-)
• HIV() is a risk factor for resistance to INH,
  RIF, and INH/RIF.

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Copathogenicity of TB and HIV

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

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How HIV Changes TB

• HIV infection makes TB
• More common
• More difficult to diagnose
• More difficult to treat Multiple concomitant
  infections, drug-drug interactions, adverse
  side-effects, relapse, re-infection,
  drug-resistance
• More difficult to cure 5-fold increase in
  mortality

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How HIV Changes TB

• HIV mediated immunosuppression impairs granuloma
  formation cannot contain the bacilli and cannot
  form cavities
• Extrapulmonary disease
• Atypical chest radiographs
• Increased lower lobe involvment
• Lower concentrations of bacteria in sputum

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CASE

• Mr. K. is a 35 year old male from Haiti who was
  diagnosed with HIV three years ago. He has
  refused treatment with ART. He has a 0 mm PPD. He
  now presents with cough, a 10 lb weight loss over
  the past 2 months, and night sweats.

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CASE
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Which of the Following is True?

• A. TB is unlikely as his PPD is 0 mm.
• B. Respiratory isolation precautions should
  be instituted
• C. Start INH to prevent active TB
• D. Pulmonary TB is unlikely with a normal CXR

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Which of the Following is True?

• A. TB is unlikely as his PPD is 0 mm.
• B. Respiratory isolation precautions should
  be instituted
• C. Start INH to prevent active TB
• D. Pulmonary TB is unlikely with a normal CXR

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OUTLINE

• TB Epidemiology
• TB Transmission
• TB-HIV copathogenicity
• TB Diagnosis
• TB Treatment
• TB Treatment in HIV patients
• TB and HIV a recipe for resistance
• LTBI?
• Future

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Diagnosis Of TB

• Key
• THINK TB

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WHEN???

• An epidemiologic link is identified
• And
• Pt is immunosuppressed
• And / OR
• The patient presents with subacute symptoms
  (cough, fever, weight loss, sweats)

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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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TB DIAGNOSIS

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

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TB DIAGNOSIS

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

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TB DIAGNOSIS

• Smear
• Cheap rapid
• Only 40-60 positive in cases of active TB , and
  much lower in HIV

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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

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TB DiagnosisNucleic Acid Amplification
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TB Disease Diagnosis

• Nucleic Acid Amplification
• Results available in 8 hours
• Specificity 99 on smear() specimens
• Sensitivity 70-80 on multiple respiratory
  specimens
• 30-50 per test

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NAA testing should be performed on a respiratory
specimen from each patient with signs and
symptoms of active pulmonary TB disease for whom
a diagnosis of TB is being considered (i.e., TB
suspect), but has not been established.

• CDC Report - Uses of Nucleic Acid Amplification
  Tests for the Diagnosis of Tuberculosis 2009

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Case

• A 45 year old male is a recent arrival from South
  Africa. He presents with cough, fevers and weight
  loss for 2 months. He is newly diagnosed with HIV
  and has a CD4 count of 8. He has a 10 mm PPD and
  his CXR shows bilateral lower lobe infiltrates.
  He was placed on respiratory isolation and 3
  sputum specimens were negative for AFB and MTD.
  Cultures are pending. He was started on
  Moxifloxacin 800 mg qd for presumed bacterial
  pneumonia and he states that his cough is
  somewhat improved. He denies prior TB treatment.

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Which of the following is a true statement?

• A. Active pulmonary tuberculosis infection in
  this patient has not been ruled out
• B. The respiratory precautions can be safely
  discontinued now that he has 3 negative sputa for
  MTB
• C. He is at low risk for MDR-TB since he was
  never treated for TB in the past
• D. Moxifloxacin is a good choice because it has
  broadspectrum antibacterial coverage and has been
  shown to have potent activity against
  mycobacterial tuberculosis

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Which of the following is a true statement?

• A. Active pulmonary tuberculosis infection in
  this patient has not been ruled out
• B. The respiratory precautions can be safely
  discontinued now that he has 3 negative sputa for
  MTB
• C. He is at low risk for MDR-TB since he was
  never treated for TB in the past
• D. Moxifloxacin is a good choice because it has
  broadspectrum antibacterial coverage and has been
  shown to have potent activity against
  mycobacterial tuberculosis

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OUTLINE

• TB Epidemiology
• TB Transmission
• TB-HIV Copathogenicity
• TB Diagnosis
• TB Treatment
• TB Treatment in HIV patients
• TB and HIV A Recipe for Resistance?
• LTBI

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How the Battle against TB was won... and almost
Lost
1944 Streptomycin Introduced 1946 Youmans
recognizes SM resistance 1951 Need for multi-drug
therapy 1952 PZA introduced 1952 INH
introduced 1961 EMB introduced 1966 Rifampin
introduced
The Lord hath created medicines out of the earth
and he that is wise will not abhor them.
-Waksman Noble Prize 1952
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General Principles of Chemotherapy

• With few exceptions, current recommendations for
  the treatment of patients with HIV and TB are the
  same as those for the treatment of TB in HIV
  negative adults

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General Principles of Chemotherapy

• Goals
• Minimize further transmission by rendering
  patient non-infectious rapidly
• Achieve cure
• Prevent death and relapse
• Prevent emergence of drug resistance

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General Principles of Chemotherapy

• Overcoming Resistance
• 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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Development of Resistance
INH
I
I
I
I
I
INH
I
I
INH
RIF
RIF
I
INH
INH
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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
• Under-use of smears, over-reliance on CXR, choice
  of drugs, dosages and failure to address
  non-adherence
• Program factors
• Intermittent drug supply, lack of training, no
  DOT, lack of lab infrastructure
• Patient factors
• Irregular self administration, side-effects,
  inability to penetrate, malabsorption,
  misunderstanding, substance abuse, pregnancy,
  mental illness

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TB Tx (CDC Guidelines 2003)

• Start with 4 drugs in all patients
• INH, RIF, PZA and EMB until sensitivities return
• After 2 months of therapy, D/C PZA
• Continue INH RIF for 4 more months-total 6
  months
• Must have culture conversion by 2 months
• 6 month regimen good for HIV(-) and () in most
  cases
• TIW in HIV () at a minimum and only after 2
  months of daily
• Monitor adherence and toxicity
• DOT is standard of care in US for HIV patients

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• The responsibility for successful treatment is
  clearly assigned to the public health program, or
  private provider, not to the patient
• CDC guidelines 2002

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Case

• A 19 year old US born woman presents with night
  sweats and an enlarged left-side cervical lymph
  node. She is newly diagnosed with HIV and not
  currently on ART. A needle biopsy of the node
  reveals extensive necrotizing granulomas. Her
  grand-mother was treated for pulmonary TB 2 years
  ago.

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Case

• PCR of the biopsy reveals M. Tuberculosis. You
  start the standard 4 drug regimen and await final
  cultures and sensitivities.
• HAART is initiated around the same time.
• Three weeks later, she presents to your clinic
  with new fevers 102 F, and the lymph node is now
  larger than before

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At this point, you do all of the following except

• A. Stop TB medications and search for an
  alternate diagnosis and express concern that this
  might be a lymphoma
• B. Evaluate for non-compliance
• C. Evaluate for immune reconstitution with
  inflammatory response (IRIS)
• D. Check sensitivities for drug resistance

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At this point, you do all of the following except

• A. Stop TB medications and search for an
  alternate diagnosis and express concern that this
  might be a lymphoma
• B. Evaluate for non-compliance
• C. Evaluate for immune reconstitution with
  inflammatory response (IRIS)
• D. Check sensitivities for drug resistance

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OUTLINE

• TB Epidemiology
• TB Transmission
• TB-HIV Copathogenicity
• TB Diagnosis
• TB Treatment
• TB Treatment in HIV patients
• TB and HIV A Recipe for Resistance?
• LTBI

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TB Tx in HIV Patients

• IRIS
• When to initiate ART
• Role of Rifabutin
• Selection of ART
• Drug-Drug interactions and Rifampin
• Role of Cotrimoxazole

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TB-Associated IRIS

• 2 Forms
• 1. Paradoxical IRIS TB/HIV patient undergoing
  treatment develops a paradoxical worsening of
  symptoms after starting HAART
• 2. Unmasking IRIS HIV patient with
  unrecognized TB starts HAART and then develops
  clinical manifestations of TB

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When to initiate ART?

• Optimal timing remains controversial
• No randomized, controlled clinical trials
• Fear of IRIS v. fear of high mortality rates in
  untreated co-infected patients
• In most cases hold HAART until completion of
  intensive phase of TB treatment

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Role of Rifabutin

• Complex drug-drug interactions between rifamycins
  and PIs and NNRTIs
• Leads to toxicity and increased frequency of
  adverse events
• Rifabutin structurally similar to Rifampin but
  has minimal p-450 induction activity
• Can be used with PIs and NNRTIs

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Role of Rifabutin

• Always adjust Rifabutin and ART according to
  updated CDC guidelines found at
• www.cdc.gov/tb/tb_hiv_drugs/

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Which ART?

• Efavirenz (e.g. Atripla)
• Easy 1 pill, well tolerated
• Raise dose of Rifabutin 450mg 600mg TIW
• Nelfinavir
• Kaletra
• KEY Constantly Changing!!!!

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Role of Cotrimoxazole

• Cotrimoxazole prophylaxis associated with
  decreased morbidity and hospital
• Studies performed in TB patients in a setting
  with high HIV seroprevalence

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Key Points to Remember

• Use Rifabutin instead of Rifampin it is a less
  potent inducer of CYP
• Refer to http//www.cdc.gov/tb/tb_hiv_drugs/defa
  ult.htm for recommendations on dosing rifamycins
  with HAART agents
• Daily regimens in TB/HIV cases for a minimum of 2
  months

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Key Points to Remember

• Consider consultation with an expert early
  1-800-4TB-INFO and National HIV Consultation
  Service 800-933-3413
• If TB patient not on HAART, consider delaying
  HAART until clinical response to TB meds Avoid
  starting all at once
• Avoid use of Quinolones for presumed CAP until TB
  has been ruled out

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OUTLINE

• TB Epidemiology
• TB Transmission
• TB-HIV Copathogenicity
• TB Diagnosis
• TB Treatment
• TB Treatment in HIV patients
• TB and HIV A Recipe for Resistance?
• LTBI

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Resistance

• Monoresistance resistance to one drug of the
  first-line drugs
• Multi-drug resistance resistance to INH and
  Rifampin
• Extensively-drug resistance XDR-TB resistance
  to INH and Rifampin PLUS any fluoroquinolone and
  any of the second-line injectables Amikacin,
  kanamycin or capreomycin

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Global Burden of Drug Resistance

• True scale of the problem unknown
• In 2008, the WHO reported the highest rates of
  MDR-TB ever with about 500,000 new cases (5 of
  all cases)
• Highest rates in countries of former Soviet Union
  and China
• XDR-TB reported in 45 countries
• Treatment of the MDR cases alone would cost more
  than all the care of the drug-susceptible cases
  combined

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Is HIV a Risk Factor For Resistance?

• MDR-TB more common in HIV
• Acquired Rifampin monoresistance more common in
  HIV
• Malabsorption?
• Extrapulmonary MTB?
• Non-adherence?

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DX OF TB DRUG RESISTANCE

• Conventional methods (indirect/proportion
  method)
• Line Probe Assays
• Hain detects presence of TB complex and gene
  mutations associated with Rifampin resistance
  (rpoB ) and INH resistance (kat G and inhA)
• In smear positive specimens
• Rifampin resistance Sensitivity (98.9)
  Specificity (99)
• INH resistance Sensitivity (94) Specificity
  (99)

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DX OF TB DRUG RESISTANCE

• 4 TB Regional Training and Medical Consultation
  Centers (RTMCCs)
• Southeastern National TB Center1-800-4TB-INFO
• HAIN testing in selected cases

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OUTLINE

• TB Epidemiology
• TB Transmission
• TB-HIV Copathogenicity
• TB Diagnosis
• TB Treatment
• TB Treatment in HIV patients
• TB and HIV A Recipe for Resistance?
• LTBI

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CASE

• 25 year old male patient who is HIV positive. He
  states that his brother was recently diagnosed
  with active pulmonary TB. A PPD was performed and
  is 0 mm. The patient denies symptoms of active TB
  disease. His CXR is normal.

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True or False

• He should be offered treatment for latent TB
  infection even though his PPD is 0 mm

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TRUE
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Tuberculin Test
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Sensitivity and Specificity of the PPD

• Depending on prevalence of disease in population
  you are testing and geographical area
• up to 20 of positive reactions might be false
  positives
• up to 20 of individuals with active TB may be
  false negative

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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 in HIV

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AJRCCM 2000 161S221-247.
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Targeted Testing

• Targeted tuberculin testing programs should be
  designed for one primary purpose
• To identify persons at high risk for TB who
  would benefit by treatment of LTBI
• EVERYBODY WITH HIV SHOULD BE TESTED ANNUALLY
• The Decision to Tuberculin Test is the Decision
  to Treat (and Complete)

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Criteria for Tuberculin Positivity By Risk
Groupgt 5 mm induration

• HIV positive persons
• Recent contacts of TB case
• Fibrotic changes on chest radiograph c/w with old
  TB
• Patients with organ transplants and other
  immunosuppressed patients (receiving the
  equivalent of gt 15mg/day of prednisone for gt 1
  month)
• ? In patients who will be treated with Infliximab
  (TNF-? Inhibitors)
• Risk of TB in patients treated with
  corticosteroids increases with higher dose and
  longer duration

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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
• Rif/PZA daily for 2 months as effective as 9
  months of INH
• Rifabutin may be substituted for RIF in pts on
  Protease Inhibitors
• Rif/PZA twice weekly not as well studied
• RIF for 4 months as effective as INH for 9 months

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Monitoring

• Active TB should be ruled out before starting RX
• Baseline Labs and monthly LFTs/CBC indicated in
  HIV

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Assure the Treatment Until Cure of Every
Tuberculosis Patient!
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Common Obstacles

• Adherence
• Resistance

HIV
TB
90
Common Future

• Vaccine

HIV
TB
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TB AND HIV A PARTNERSHIP FOR LIFE
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SNTC-A.G. HOLLEY TB HOTLINE
1-800-4TB-INF0