Tuberculosis and
HIV/AIDS
Rafael Laniado-Laborin MD, MPH, FCCP
Universidad Autónoma de Baja California
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; 7:S328
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
How frequent is the coinfection?
TB cases in persons with HIV co-infection, USA
1993-2003 (25-44 years old)
35
30
29
29
26
(%)
25
25
21
20
20
15
19
17
16
16
16
10
5
0
1993
1994
1995
1996
1997
1998
1999 2000
2001
2002 2003
CDC Website, Sep 2006
TB: Border states USA & Mexico
8.3
CA
BC
41.5
4.7
AZ
25.3
SON
2.2
NM
18.7
CHI
7.5
TX
11.7
COH
NL
21.9
31.1
TAM
SOURCE: DGE MEXICO / CDC EUA
Bacteriology

MTB belongs to the
genus Mycobaterium

Mycobacterium
tuberculosis complex
o M. tuberculosis
o M. bovis
o M. africanum
o M. microti
o M. canetti
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:
o Mycobacterium avium complex (60 %)
o Mycobacterium fortuitum (20 %)
o Mycobacterium kansasii (10 %)
Pathogenesis

Tuberculosis is spread from person to person
through the air by droplet nuclei, particles <5 mm in
diameter that contain M. tuberculosis complex
Pathogenesis

4 factors determine the risk of
infection:
o the number of organisms
being expelled into the air
o the concentration of
organisms in the air
(volume of the space and
its ventilation)
o the length of time an
exposed person breathes
the contaminated air
o the immune status of the
exposed individual

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

Also, HIV-infected persons and others with
impaired cell-mediated immunity are much
more likely to develop disease if they are
infected
Pathogenesis

Inhalation and deposition in the lungs of the
tubercle bacillus leads to one of four possible
outcomes:
o
o
o
o
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)
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
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
Pathogenesis

The infected
macrophages
produce cytokines
that attract other
phagocytic cells
which eventually
form a nodular
granulomatous
structure called the
tubercle
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
Primary complex (Gohn’s)
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

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

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

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; 172:1169


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; 172:1169

The risk depends, however, on the degree of
immunosuppression—the risk of a patient
with AIDS developing tuberculosis is 170
times higher than a non immunosuppressed
person
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
Reactivation disease

Immunosuppressive conditions associated
with reactivation TB include:
o
o
o
o
o
o
HIV infection and AIDS
end-stage renal disease
diabetes mellitus
malignant lymphoma
corticosteroid use
old age
Clinical manifestations
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:
o 38% exclusively pulmonary
o 30% extrapulmonary
o 32% pulmonary + extrapulmonary
Systemic manifestations

Fever (37-80%)

Weight loss

Night sweats

Loss of appetite

Malaise
Pulmonary TB

Cough: is the most common symptom

Sputum, hemoptysis

Pleuritic pain

Dyspnea
Radiographic
manifestations
Radiographic findings

PTB is almost associated to radiographic
abnormalities

Patients with HIV and PTB might have a
normal chest x-ray
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
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
Disseminated tuberculosis
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
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
Disseminated TB
Laboratory diagnosis
Diagnosis

Microscopy:
o 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.
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
Mycobacteria cultures
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)
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 HIVnegative patients.
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
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
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
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
Molecular methods


The application of nucleic acid (DNA and
RNA) amplification techniques—the
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
Diagnosis of LTBI
TST is considered as positive if > 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 ( >15
mg/day of prednisone)

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; 172:1169
IFN- assays


Patient’s 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; 28:1-3
IFN- assays

There are two different assay formats:
o ELISA detection after blood is incubated in a tube
with ESAT6/CPF10 antigens (Quantiferon-Gold)
o ELISA immunospot technique (T-Spot.TB)


Advantage: one blood sample; no repeated
visits as in TST
Disadvantage: cost
Eur Respir J 2006; 28:1-3
IFN- assays

These assays are not as sensitive for
diagnosing active TB since IFN- responses
decline as TB develops
Eur Respir J 2006; 28:1-3
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; 28:24-30
Guidelines for using the QF-Gold test
CDC 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
Guidelines for using the QF-Gold test
CDC 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
Treatment
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


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
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
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
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 (>400
mg BID)
Am J Respir Crit Care Med 2001; 164:7-12
Antituberculous drug interactions

Even if rifabutin is substituted for RIF, care
should be exercised in the use of the
protease inhibitor saquinavir and the nonnucleoside reverse transcriptase inhibitors as
rifabutin decreases their levels, with the risk
of selection of drug resistant viruses
Immune reconstitution syndrome

It appears usually after two weeks of ARV
treatment

Most of the patients have far advance AIDS
o median CD4+: 35 cells/mm3
o median viral load: 581,694 copies/mL
Paradoxical reactions (immune
reconstitution syndrome)

These manifest as fever, enlargement of
affected lymph nodes, and a worsening of the
radiological appearance
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.
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
Tcell count
Int J Tuberc Lung Dis 2005; 9:946
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 <350 cells/mm3
Those with Stage I and II disease should only
receive ART for CD41 T-cell counts <200
cells/mm3
Int J Tuberc Lung Dis 2005; 9:946
Treatment of LTBI
Incidence of active TB in PPD positive
subjects according to risk factor
Risk factor
TB infection<1 year
TB infection 1-7 years
HIV infection
IV drug use (HIV negative)
x-ray abnormality (old TB)
Weight loss >15%
Weight loss 10-14%
TB cases /1000
patient-years
12.9
1.6
35-162
10
2-13.6
2.6
2.0
Treatment of LTBI


It has been used for more than 30 years
Evidence is classified as:
o
o
o
o
o
o
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

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; 172:1169

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; 172:1169
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
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
Drugs
Duration
(months)
Interval
HIV-
HIV+
A(II)
B(II)
B(I)
B(II)
B(II)
C(II)
A(II)
B(II)
C(I)
C(I)
A(I)
C(I)
B(II)
B(II)
INH
9
INH
6
RIF-PZA
2
2-3
Daily
Bi-weekly
Daily
Bi-weekly
Daily
Bi-weekly
RIF
4
Daily

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; 172:1169
BCG
VACCINATION
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%
BCG: a meta-analysis

Meta-analysis of over 1,200 articles from
international publications

Only 14 prospective trials and 12 casecontrol studies met the selection criteria
JAMA 1994; 271:698-702
BCG: a meta-analysis

Combining data from the trials the RR for TB
among those vaccinated with BCG was 0.49
(95%CI, 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 (95%CI 0.39 to 0.64)
JAMA 1994; 271:698-702
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 2003;81:61
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

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
Adverse events associated with BCG
vaccination in children infected with HIV
Dissemination
0-31%
Lymphadenitis
0-24%
Bull World Health Org 2003;81:61
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 2003;81:61