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HIV AND TUBERCULOSIS: A SPARK THAT LIGHTS THE FIRE

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Title: HIV AND TUBERCULOSIS: A SPARK THAT LIGHTS THE FIRE


1
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
2
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

3
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

4
  • The Lord shall smite thee with a consumption and
    with a fever, and with an inflammation…and they
    shall pursue thee until thou perish.

Deuteronomy 2822
5
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)

6
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

7
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

9
We have to stop people living with HIV from
dying of tuberculosis
  • Dr. Michael Sidibe, 2009
  • Director of UNAIDS

10
Reported TB Cases United States, 19822008
No. of Cases
Year
Updated as of April 23, 2008.
11
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)
12
TB Morbidity United 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.
13
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

14
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

15
Tuberculosis Cases by HIV Test Status Florida,
2008
n161
Percentages have been rounded and may not equal
100
Provisional data from TIMS Indeterminate cases
were less than 1.
16
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

17
Everyone knows the air is terribly infected from
the numerous mortals who have died exhaling it
  • Moby Dick
  • Herman Melville

18
Transmission Of Tuberculosis
19
Pathogenesis of Tuberculosis
20
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

21
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

22
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.

23
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(-) !!)

24
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

25
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

26
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.

27
CASE
28
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

29
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

30
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

31
Diagnosis Of TB
  • Key
  • THINK TB

32
WHEN???
  • An epidemiologic link is identified
  • And
  • Pt is immunosuppressed
  • And / OR
  • The patient presents with subacute symptoms
    (cough, fever, weight loss, sweats)

33
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34
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35
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

36
TB DIAGNOSIS
  • Chest X-Ray
  • 95 of HIV(-) cases with upper lobe infiltrates
    and/or cavities

37
TB DIAGNOSIS
  • Up to 30 of HIV (), active TB cases will have
    no infiltrates or cavities

38
TB DIAGNOSIS
  • Smear
  • Cheap rapid
  • Only 40-60 positive in cases of active TB , and
    much lower in HIV

39
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

40
TB Diagnosis Nucleic Acid Amplification
41
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

42
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

43
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.

44
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

45
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

46
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

47
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
48
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

49
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

50
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

51
Development of Resistance
INH
I
I
I
I
I
INH
I
I
INH
RIF
RIF
I
INH
INH
52
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

53
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

54
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

55
  • The responsibility for successful treatment is
    clearly assigned to the public health program, or
    private provider, not to the patient
  • CDC guidelines 2002

56
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.

57
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

58
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

59
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

60
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

61
TB Tx in HIV Patients
  • IRIS
  • When to initiate ART
  • Role of Rifabutin
  • Selection of ART
  • Drug-Drug interactions and Rifampin
  • Role of Cotrimoxazole

62
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

63
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

64
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

65
Role of Rifabutin
  • Always adjust Rifabutin and ART according to
    updated CDC guidelines found at
  • www.cdc.gov/tb/tb_hiv_drugs/

66
Which ART?
  • Efavirenz (e.g. Atripla)
  • Easy 1 pill, well tolerated
  • Raise dose of Rifabutin 450mg 600mg TIW
  • Nelfinavir
  • Kaletra
  • KEY Constantly Changing!!!!

67
Role of Cotrimoxazole
  • Cotrimoxazole prophylaxis associated with
    decreased morbidity and hospital
  • Studies performed in TB patients in a setting
    with high HIV seroprevalence

68
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

69
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

70
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

71
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

72
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

73
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?

74
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)

75
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

76
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

77
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.

78
True or False
  • He should be offered treatment for latent TB
    infection even though his PPD is 0 mm

79
TRUE
80
Tuberculin Test
81
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

82
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

83
AJRCCM 2000 161S221-247.
84
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)

85
Criteria for Tuberculin Positivity By Risk
Group gt 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

86
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

87
Monitoring
  • Active TB should be ruled out before starting RX
  • Baseline Labs and monthly LFTs/CBC indicated in
    HIV

88
Assure the Treatment Until Cure of Every
Tuberculosis Patient!
89
Common Obstacles
  • Adherence
  • Resistance

HIV
TB
90
Common Future
  • Vaccine

HIV
TB
91
TB AND HIV A PARTNERSHIP FOR LIFE
92
SNTC-A.G. HOLLEY TB HOTLINE
1-800-4TB-INF0
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