Rafael Laniado-Laborin MD, MPH, FCCP

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Tuberculosis and HIV/AIDS

• Rafael Laniado-Laborin MD, MPH, FCCP
• Universidad Autónoma de Baja California

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Background

• The World Health Organization (WHO) estimates
  that approximately one third of the total
  population of the world harbors tubercle bacilli
  in a latent form
• A new infection occurs every second

Int J Tuberc Lung Dis 2003 7S328
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Background

• The WHO also estimates that each year more than 9
  million new cases of tuberculosis occur and
  approximately 2 million persons die from the
  disease
• One case can infect from 10 to 15 people

IUTLD-NAR Meeting 2006
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How frequent is the co-infection?
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TB cases in persons with HIV co-infection, USA
1993-2003 (25-44 years old)
CDC Website, Sep 2006
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TB Border states USA Mexico
8.3
CA
2.2
4.7
NM
AZ
7.5
BC
TX
25.3
41.5
18.7
SON
11.7
CHI
COH
NL
31.1
21.9
TAM
SOURCE DGE MEXICO / CDC EUA
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Bacteriology

• MTB belongs to the genus Mycobaterium
• Mycobacterium tuberculosis complex
• M. tuberculosis
• M. bovis
• M. africanum
• M. microti
• M. canetti

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Nontuberculous mycobacterium (MOTT)

• In the US up 30 of the isolates are NTM (rate
  1.8 per 100,000 h.
• The most common NTM are
• Mycobacterium avium complex (60 )
• Mycobacterium fortuitum (20 )
• Mycobacterium kansasii (10 )

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Pathogenesis

• Tuberculosis is spread from person to person
  through the air by droplet nuclei, particles lt5
  mm in diameter that contain M. tuberculosis
  complex

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Pathogenesis

• 4 factors determine the risk of infection
• the number of organisms being expelled into the
  air
• the concentration of organisms in the air
  (volume of the space and its ventilation)
• the length of time an exposed person breathes the
  contaminated air
• the immune status of the exposed individual

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• HIV-infected persons and others with impaired
  cell-mediated immunity are thought to be more
  likely to become infected with M. tuberculosis
  after exposure than persons with normal immunity

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• Also, HIV-infected persons and others with
  impaired cell-mediated immunity are much more
  likely to develop disease if they are infected

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Pathogenesis

• Inhalation and deposition in the lungs of the
  tubercle bacillus leads to one of four possible
  outcomes
• immediate clearance of the organism
• chronic or latent infection
• rapidly progressive disease (or primary disease)
• active disease months to years after the
  infection (reactivation disease)

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Pathogenesis

• Only 5 to 10 percent of patients with no
  underlying medical problems who become infected
  develop active disease in their lifetime
• The risk increases markedly in patients with AIDS
  

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Pathogenesis

• Once they are inhaled, the bacilli will reach
  the distal bronchioles and alveoli
• Inside the alveolar macrophages M. tuberculosis
  will multiply slowly (once every 24-32 hours) and
  kill the cell

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Pathogenesis

• The infected macrophages produce cytokines that
  attract other phagocytic cells which eventually
  form a nodular granulomatous structure called the
  tubercle

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Pathogenesis

• If the bacterial replication is not controlled,
  the tubercle enlarges and the bacilli enter the
  local draining lymph nodes
• The lesion produced by the expansion of the
  tubercle into the lung parenchyma and lymph node
  involvement is called the Ghon complex

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Primary complex (Gohns)
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Pathogenesis

• Failure by the host to mount an effective CMI
  response and tissue repair leads to progressive
  destruction of the lung
• If the bacterial growth continues to remain
  unchecked, the bacilli may spread hematogenously
  to produce disseminated TB

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• HIV-infected persons, especially those with low
  CD4 cell counts, develop tuberculosis disease
  rapidly after becoming infected with M.
  tuberculosis
• Up to 50 percent of such persons may do so in the
  first two years after infection with M.
  tuberculosis

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• Conversely, an individual who has a prior latent
  infection with M. tuberculosis (not treated) and
  then acquires HIV infection will develop
  tuberculosis disease at an approximate rate of 5
  to 10 percent per year

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• Voluntary HIV counseling and testing is
  recommended for all patients with TB and should
  be considered the standard of care

Am J Respir Crit Care Med 2005 1721169
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• Physicians who provide primary care to persons
  with HIV infection or populations at increased
  risk for HIV infection should maintain a high
  index of suspicion for TB
• Every patient in whom HIV infection has been
  newly diagnosed should be assessed for the
  presence of TB or LTBI

Am J Respir Crit Care Med 2005 1721169
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• The risk depends, however, on the degree of
  immunosuppressionthe risk of a patient with AIDS
  developing tuberculosis is 170 times higher than
  a non immunosuppressed person

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Reactivation disease

• Reactivation TB results when the persistent
  bacteria in a host suddenly proliferate
• While immunosuppression is clearly associated
  with reactivation TB, it is not clear what host
  factors specifically maintain the infection in a
  latent state for many years and what triggers the
  latent infection to become overt

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Reactivation disease

• Immunosuppressive conditions associated with
  reactivation TB include
• HIV infection and AIDS
• end-stage renal disease
• diabetes mellitus
• malignant lymphoma
• corticosteroid use
• old age

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Clinical manifestations
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Clinical manifestations

• In immunocompetent individuals, 85 of the cases
  are exclusively pulmonary, and the rest have
  extrapulmonary manifestations
• This distribution is modified in HIV patients
• 38 exclusively pulmonary
• 30 extrapulmonary
• 32 pulmonary extrapulmonary

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Systemic manifestations

• Fever (37-80)
• Weight loss
• Night sweats
• Loss of appetite
• Malaise

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Pulmonary TB

• Cough is the most common symptom
• Sputum, hemoptysis
• Pleuritic pain
• Dyspnea

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Radiographic manifestations
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Radiographic findings

• PTB is almost associated to radiographic
  abnormalities
• Patients with HIV and PTB might have a normal
  chest x-ray

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Radiographic findings

• In patients with HIV infection, the nature of the
  x-ray findings depends to a certain extent on the
  degree of immunocompromise produced by the HIV
  infection
• TB that occurs relatively early in the course of
  HIV infection tends to have the typical x-ray
  findings of the immunocompetent patient

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Radiographic findings

• With more advanced HIV disease the radiographic
  findings become more "atypical" cavitations is
  uncommon, and lower lung zone or diffuse
  infiltrates and intrathoracic adenopathy are
  frequent

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Disseminated tuberculosis
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Disseminated tuberculosis

• The term "miliary" is derived from the visual
  similarity of some disseminated lesions to millet
  seeds
• Grossly, these lesions are 1- to 2-mm yellowish
  nodules that, histologically, are granulomas
• Thus disseminated tuberculosis is sometimes
  called "miliary" tuberculosis

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Disseminated TB

• Because of the multisystem involvement in
  disseminated tuberculosis, the clinical
  manifestations are protean
• The presenting symptoms and signs are generally
  nonspecific and are dominated by systemic
  effects, particularly fever, weight loss, night
  sweats, anorexia, and weakness
• Other symptoms depend on the relative severity of
  disease in the organs involved

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Disseminated TB
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Laboratory diagnosis
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Diagnosis

• Microscopy
• this is principally applied to sputum but other
  specimens include bronchoalveolar lavage fluid,
  gastric washings, laryngeal swabs, cerebrospinal
  fluid, pleural, pericardial and peritoneal
  effusions, fine needle lymph node aspirates, bone
  marrow aspirates, and tissue biopsies.

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Diagnosis

• A wide range of acid-fast smear positivity has
  been reported (31 to 81 percent), but most
  studies find a 50 to 60 percent yield
• The yield is substantially higher (85 to 100
  percent) on sputum culture

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Mycobacteria cultures
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Diagnosis

• In patients infected with HIV, a positive smear
  for acid-fast bacilli (AFB) is very specific for
  Mycobacterium tuberculosis (MTB), even in a
  setting with a high incidence of Mycobacterium
  avium complex (MAC)

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Diagnosis

• At San Francisco General Hospital, for example,
  248 of 271 (92 percent) expectorated sputum
  samples which were positive for AFB grew MTB on
  culture
• This value is comparable to that found in
  HIV-negative patients.

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Diagnosis

• Urine cultures Although genitourinary TB rarely
  occurs in the absence of other sites of
  extrapulmonary disease, it is frequently involved
  in disseminated TB, even in the absence of pyuria
• In one series, for example, 77 HIV-infected
  patients with extrapulmonary TB whose urine was
  sent for culture grew MTB

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Diagnosis

• Invasive testing should be performed when
  noninvasive studies yield no immediate answer and
  the wait for culture results would be detrimental
  to the patient
• Bronchoscopy is a sensitive technique for
  diagnosing TB
• An immediate diagnosis can be made from AFB
  smears in about one-half of patients, and the
  sensitivity of cultures approaches 100 percent

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Diagnosis

• The central nervous system is frequently involved
  in disseminated TB
• Given the number of opportunistic infections
  affecting the central nervous system in AIDS,
  there should be a low threshold for collecting
  CSF

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Diagnosis

• In a patient with suspected miliary disease and a
  negative sputum examination, bone marrow biopsy
  as well as blood cultures should be performed
• Blood cultures are positive in 49 percent of
  patients with disseminated disease and CD4 counts
  less than 100/mm3

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Molecular methods

• The application of nucleic acid (DNA and RNA)
  amplification techniquesthe polymerase chain
  reaction (PCR) and the ligase chain reaction
  (LCR)is the subject of intense research activity
• As a result, a number of rapid, sensitive, and
  specific test kits are commercially available

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Diagnosis of LTBI
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TST is considered as positive if gt 5 mm

• Contacts of an active TB case
• Subjects with a chest x-ray anomalies (fibrosis)
  suggestive of old (untreated) TB
• Immunosuppression (including HIV)
• Drug induced immunosuppression ( gt15 mg/day of
  prednisone)

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• Patients with 5 mm or more of induration be
  considered to have a positive test and should
  receive, in addition to chest x-rays, a clinical
  evaluation to rule out TB

Am J Respir Crit Care Med 2005 1721169
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IFN-? assays

• Patients T cells release IFN-? when exposed to
  mycobacterial antigens
• The genes encoding for two antigenic targets,
  ESAT6 and CFP10 are absent in the BCG vaccine
  strain and most environmental mycobacteria

Eur Respir J 2006 281-3
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IFN-? assays

• There are two different assay formats
• ELISA detection after blood is incubated in a
  tube with ESAT6/CPF10 antigens (Quantiferon-Gold)
• ELISA immunospot technique (T-Spot.TB)
• Advantage one blood sample no repeated visits
  as in TST
• Disadvantage cost

Eur Respir J 2006 281-3
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IFN-? assays

• These assays are not as sensitive for diagnosing
  active TB since IFN-? responses decline as TB
  develops

Eur Respir J 2006 281-3
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75 individuals with active TB and control group
(HS students with ?risk of
infection)
Active TB Immuno? Controls (specificity)
TST 72 37 82
T-Spot.TB 96 100 86
QF-Gold 77 75 92
Eur Respir J 2006 2824-30
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Guidelines for using the QF-Gold testCDC
2005/54(RR15)49-55

• FDA approved
• Diagnosing infection with M. tuberculosis
  including both TB disease and LTBI
• QF-G can be used in all circumstances in which
  the TST is used

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Guidelines for using the QF-Gold testCDC
2005/54(RR15)49-55

• QF-G can be used in place of (and not in addition
  to) TST
• A positive QF-G result should prompt the same
  public health and medical interventions as a
  positive TST result

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Treatment
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Treatment of HIV related tuberculosis

• The standard WHO recommended antituberculosis
  regimen is a six month course of RIF and INH,
  PZA, together with ETH (or SM) during the first
  two months of treatment
• Supplementation with daily pyridoxine (vitamin
  B6) to prevent isoniazid induced neuropathy is
  now routine

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• There is little or no difference in relapse rate
  between HIV infected and uninfected patients when
  RIF based short course treatment is used
• Thus, in the absence of drug resistance, the
  standard short course just described is
  recommended

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Antituberculous drug interactions

• A number of interactions between antituberculosis
  agents and other drugs have been described
• Most interactions are associated with RIF due to
  its ability to induce cytochrome CYP450 enzymes
  in the liver which affect the metabolism of many
  other drugs

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Antituberculous drug interactions

• The current recommendation is to replace RIF by
  rifabutin, a much less powerful inducer of
  cytochrome enzymes, and to start or continue with
  the antiretroviral drugs

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Management recommendations for the use of ARV
antituberculosis drugs

• Frequent communication between TB and HIV care
  providers
• Adjust dose of rifabutin as needed
• Use rifampin with efavirenz or ritonavir (gt400 mg
  BID)

Am J Respir Crit Care Med 2001 1647-12
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Antituberculous drug interactions

• Even if rifabutin is substituted for RIF, care
  should be exercised in the use of the protease
  inhibitor saquinavir and the non-nucleoside
  reverse transcriptase inhibitors as rifabutin
  decreases their levels, with the risk of
  selection of drug resistant viruses

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Immune reconstitution syndrome

• It appears usually after two weeks of ARV
  treatment
• Most of the patients have far advance AIDS
• median CD4 35 cells/mm3
• median viral load 581,694 copies/mL

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Paradoxical reactions (immune reconstitution
syndrome)

• These manifest as fever, enlargement of affected
  lymph nodes, and a worsening of the radiological
  appearance

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Paradoxical reactions (immune reconstitution
syndrome)

• These reactions are not indicative of treatment
  failure and usually subside spontaneously
• Treatment should not be modified but short
  courses of steroids may be required for severe
  paradoxical reactions.

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When should ART be started?

• ARVs should be given to those with WHO Stage IV
  disease, including individuals with
  extra-pulmonary TB, regardless of CD4
  T-cell count

Int J Tuberc Lung Dis 2005 9946
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When should ART be started?

• Those with Stage III conditions, including
  individuals with pulmonary TB (PTB), should have
  CD4 T-cell counts taken into consideration
  treatment is recommended when counts are lt350
  cells/mm3
• Those with Stage I and II disease should only
  receive ART for CD41 T-cell counts lt200 cells/mm3

Int J Tuberc Lung Dis 2005 9946
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Treatment of LTBI
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Incidence of active TB in PPD positive subjects
according to risk factor
Risk factor TB cases /1000 patient-years
TB infectionlt1 year 12.9
TB infection 1-7 years 1.6
HIV infection 35-162
IV drug use (HIV negative) 10
x-ray abnormality (old TB) 2-13.6
Weight loss gt15 2.6
Weight loss 10-14 2.0
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Treatment of LTBI

• It has been used for more than 30 years
• Evidence is classified as
• A preferred treatment
• B acceptable alternative
• C offer if A and B are not an option
• I randomized clinical trial
• II clinical trail not randomized
• III experts opinion

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• Targeted testing and treatment for LTBI are
  strongly recommended at the time the diagnosis of
  HIV infection is established (AII)

Am J Respir Crit Care Med 2005 1721169
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• Persons with known or suspected HIV infection who
  have contact with a patient with infectious
  pulmonary TB should be offered a full course of
  treatment for LTBI regardless of the initial
  result of tuberculin skin testing once active TB
  has been ruled out (AII)

Am J Respir Crit Care Med 2005 1721169
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Prophylaxis against TB in co-infected persons

• In view of the very high risk of a co-infected
  person developing active TB, and the adverse
  effect of this disease on the immune status and
  survival of the patient, there is a very good
  theoretical case for provision of prophylactic
  treatment for those at risk

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Treatment of LTBI

• In the initial studies, a 12 month course of
  isoniazid was found to lower the incidence of
  tuberculosis in co-infected persons
• Subsequently, shorter combination regimens have
  also been shown to be effective

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Drugs Duration (months) Interval HIV- HIV
INH 9 Daily Bi-weekly A(II) B(II) A(II) B(II)
INH 6 Daily Bi-weekly B(I) B(II) C(I) C(I)
RIF-PZA 2 2-3 Daily Bi-weekly B(II) C(II) A(I) C(I)
RIF 4 Daily B(II) B(II)
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• An HIV-infected patient who is severely
  immunocompromised and whose initial tuberculin
  skin test result is negative should be retested
  after the initiation of antiretroviral therapy
  and immune reconstitution, when CD4 cell counts
  are greater than 200 cells/?l (AII)

Am J Respir Crit Care Med 2005 1721169
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• BCG VACCINATION

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Is BCG effective?

• Results of randomized controlled trials (RCT) and
  case control studies (CCS) showed the protective
  efficacy against tuberculosis as uncertain and
  unpredictable, as protective efficacy varied from
  0 to 80

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BCG a meta-analysis

• Meta-analysis of over 1,200 articles from
  international publications
• Only 14 prospective trials and 12 case-control
  studies met the selection criteria

JAMA 1994 271698-702
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BCG a meta-analysis

• Combining data from the trials the RR for TB
  among those vaccinated with BCG was 0.49 (95CI,
  0.34 to 0.70) protective effect 51
• Combining data from the case-control studies, the
  OR for BCG vaccination against TB was 0.50
  (95CI 0.39 to 0.64)

JAMA 1994 271698-702
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Immunization of children at risk of infection
with HIV

• The available data is not adequate to permit
  definitive conclusions about the effectiveness of
  BCG vaccine to protect HIV-infected children or
  adults against tuberculosis

Bull World Health Org 20038161
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BCG vaccination

• There is a risk that vaccination with Bacille
  Calmette-Guérin (BCG), a living attenuated
  vaccine, will cause infectious complications in
  HIV positive persons
• There is a small increase in the incidence of
  adverse effects of BCG in the children of HIV
  infected women, but most such effects are mild

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• A consensus view currently exists, however, that
  BCG should not be given to infants with active
  HIV disease and that the vaccine is
  contraindicated in older asymptomatic children
  who are found to be HIV positive

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Adverse events associated with BCG vaccination in
children infected with HIV
Dissemination 0-31
Lymphadenitis 0-24
Bull World Health Org 20038161
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Adverse events associated with BCG vaccination in
children infected with HIV

• More than 28 cases of disseminated BCG infection
  have been reported in HIV-infected children and
  adults
• Progressive immune suppression can lead to the
  reactivation of latent BCG organisms, causing
  regional or disseminated disease

Bull World Health Org 20038161
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