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ALOK SINHA
Department of Medicine
Manipal College of Medical Sciences
Pokhara, Nepal
stem cells
Lymphocytes
Mature in B.marrow to become
“B LYMPHOCYTE”
react with free antigen directly
plasma cells
Thymus
recognise the antigen with
the help of macrophages
T cells
Helper T cells
Cytotoxic T cells
(CD4 surface protein)
activated lymphocytes enter the
tissue and meet antigen again
results in multiplication and secretion of cytokines
or immunoglobins in order to destroy the antigen
Th1 cells - involved in cell
mediated immunity.
Produce
interferon gamma,
interleukin 2 & TNF beta.
Th2 cells: play a role in
humoral responses
responsible for Atopy and
allergy
Immune response in T.B. Infection
It manages to evoke both immunity & hypersensitivity in
the body
 Immunity – Good for body
–not good for bacteria
It localizes the bacteria and clears the infection
efficiently with out causing much tissue destruction
 Hypersensitivity – good for bacteria
– not good for body
 Infection can not be localized
 Plenty of tissue destruction with on going caseation &
necrosis
Introduction
 Tuberculosis and HIV - closely linked since the
emergence of AIDS. HIV infection has
contributed to a significant increase in the
worldwide incidence of tuberculosis
 Over 4 million persons worldwide have been
infected with HIV and tuberculosis
 Most common cause of death in AIDS patients
 Have instantly clicked together & linked since
the emergence of AIDS
•Love at first sight
•No generation gap
HIV & TB both affect each other
T.B.
HIV
Effect of HIV on TB
HIV
T.B.
HIV increases the incidence of TB
Now answer these 2 questions:
• What % of world population get Mycobacterium
infection at some point in their life (without
developing active disease) ?
• Of them how many of develop active disease ?
HIV increases the T.B. infection
 It is estimated that 1/3rd population of the world
are infected by the Mycobacterium tuberculosis
 Out of them only 10% have life time chances of
developing tuberculosis
 This scenario is changing with the
advent of HIV infection
Tuberculosis normally develop
through:1. progression of recently acquired infection primary disease
2. reactivation of latent infection
3. exogenous reinfection
 Concomitant HIV infection increases the
possibility of development of T.B. in all the
above categories
 People co-infected with both HIV and latent
TB have an up to 800% greater risk of
developing active tuberculosis disease and
becoming infectious compared to people not
infected with HIV
Gohn focus
Now answer these questions:
 What
is the main lesion in post primary
T.B.
 Is there hilar lymphadenopathy
 Which lobes are predominently affected
 What is the likelihood of pleural effusion

Clinical features of HIV-associated post primary
pulmonary tuberculosis (in adults) are frequently
atypical, particularly in the late stage of HIV
infection
1.
2.
3.
4.
Non-cavitary disease -Lack of hypersensitivity
Lower lobe infiltrates
Hilar lymphadenopathy Lack of immunity
Pleural effusion
Immunity
Hypersensitivity
 Tuberculosis
can be a relatively early
manifestation of HIV-1 infection
 Risk of developing tuberculosis, and of
disseminated infection, increases as the
CD4 T-cell count decreases
Immune system is unable to contain the infection
resulting in:
An increased frequency of extrapulmonary
tuberculosis
 Positive mycobacterial blood cultures
 Atypical chest radiographic findings


Patients with extrapulmonary tuberculosis may
present with signs and symptoms specific to the
involved site, such as
 lymphadenopathy
 headache
 meningismus
 pyuria
 abscess
formation
 back pain
 abdominal pain
Increased incidence of MDR TB in HIV
• Acquired resistance (Organisms are sensitive at the
beginning) in MDR TB is associated with coinfection due to HIV & tuberculosis
• In MDRTB outbreaks approximately 90% of the
cases were HIV seropositive
• Spread of Multi Drug Resistant TB poses a
serious threat to the world health
scenario
Summary
Effect of HIV on TB:
1. Increases the incidence of TB by converting the
latent infection into active one
2. Changes the clinical features of the post primary
tuberculosis
•
•
•
•
•
3.
non-cavitary disease
lower lobe infiltrates
hilar lymphadenopathy
pleural effusion
More extrapulmonary involvement
Increased incidence of MDR TB
in HIV
T.B.
HIV
– opportunistic infection in HIV/AIDS
 Relatively early manifestation of HIV-1
infection median CD4 T-cell count was
>300 cells/mm3
 Risk of developing tuberculosis & of
disseminated infection, increases as the
CD4 T-cell count decreases
 T.B.
What is normal CD4 cell count ?
600 -1200/ml
• AIDS generally occurs when
• CD4 count is below 200/mL
• or a CD4 lymphocyte percentage below 14%
• Characterized by the appearance of opportunistic
infections, eg.:
 Tuberculosis
 Pneumocystis carinii pneumonia
 Toxoplasmosis
 Meningitis and other brain infections
 Fungal infections
 Malignancies: lymphoma, cervical Ca., Kaposi's
sarcoma

Tuberculosis acts to accelerate the clinical course
of HIV infection

5- to 160-fold increase in viral replication during
the acute phase of untreated tuberculosis leads to
increased HIV viral load
Clinical Presentation of Tuberculosis
with HIV
Diagnostic difficulties initially because the early
symptom - fever, weight loss, and malaise in
both TB & HIV are same
 Earlier in the course of HIV disease TB is more
likely to present as classical reactivation-type
disease
 Patients with advanced immuno suppression
are more likely to present with findings
consistent with primary tuberculosis

bilateral hilar lymphadenopathy with diffuse interstitial
and airspace opacities. CD4 count<200
Extensive right paratracheal
lymphadenopathy
Treatment of HIV-Related
Tuberculosis

Good, early clinical response to therapy as long
as the regimen contains INH and a Rifampicin

Sputum culture conversion & treatment failure
rates were similar to those in patients without
HIV infection
Treatment of HIV & TB together poses
many problems

Requires close monitoring because
1.
Development of resistance
Frequent drug toxicities
3. Possible drug-drug interactions
4. Paradoxical reactions
2.
Rifamycins:
 Rifampicin
or Rifampin
 Rifabutin
 Rifapentine
– long acting so only once a
week dose required

Patients treated with a once-weekly Isoniazid
/Rifapentine continuation-phase regimen
Relapse with rifamycin monoresistant T.B. In
HIV-seropositive tuberculosis
 HIV-seropositive
people with tuberculosis
should not be treated with a once-weekly
isoniazid/rifapentine regimen
Adverse drug reactions

Most commonly seen with Rifampicin


Rifampicin should be avoided/replaced
Rash - Thiacetazone should not be used in the treatment of
HIV-related tuberculosis because of skin reactions

Paresthesia – B6 should be given with INH

Incidence of drug induced hepatitis is many
times more in HIV+ TB patients - Frequent
monitoring of liver function tests are required
Drug-Drug Interactions
 Certain
antituberculosis drugs may interact
adversely with medications commonly used
by HIV-infected individuals
 Rifamycin derivatives
• Rifampicin (most
potent inducer)
• Rifabutin
• Rifapentine (less potent)
induce the hepatic cytochrome
system
P450 enzyme
 Results in increased metabolism & reduced serum
levels of certain drugs which includes
• protease inhibitors (PIs)
• nonnucleoside reverse transcriptase inhibitors
(NNRTIs)
Used for the treatment of AIDS

This results in subtherapeutic levels and the
potential development of viral resistance to these
important agents

Rifabutin can be substituted for Rifampicin in the
treatment regimen

PIs and NNRTIs affect the metabolism of rifabutin,
resulting in altered serum levels and the possibility
of drug toxicity, adjustments in rifabutin dosage
are often necessary

Patients can take the standard rifampin-based
treatment regimen if not taking PIs or NNRTIs
Paradoxical Reactions

Temporary exacerbation of symptoms, signs, or
radiographic manifestations of tuberculosis seen
after beginning ATT

Occur in HIV-infected patients with active
tuberculosis

Develop after simultaneous administration of both
antiretroviral & ATT

Due to increase in the cellular immunity caused
by ART

Diagnosis of a paradoxical reaction should be
made after a thorough evaluation to exclude other
etiologies, such as tuberculosis treatment failure
Initiation of Antiretroviral Therapy in coinfected
Patient
.
No standard regimens!
Lot of confusion & uncertainity
prevails at present
So don’t start fighting over it!
Initiation of Antiretroviral Therapy in coinfected
Patient
Treatment of tuberculosis to be initiated
immediately
 Treatment of HIV infection usually started after 2
months potentially decreasing the risk of a
paradoxical reaction
 Tuberculosis and HIV can be treated concurrently
using a Rifabutin-based regimen

Whether to start ART as soon as possible or wait
until antituberculosis treatment is well established
is not clear at present
 Decision should be made on a case-by-case basis
 If already receiving ART, regimen to be continued
and modifications to either the tuberculosis
regimen or to the antiretroviral regimen can be
made as indicated


Many of the side effects like
 GIT upset
 Rash
 Preipheral neuropathy
 Flu like symptoms
Can be due to both ATT or ART

In case of ATT, they can be with held and started
one by one again

This can not be done with ART – resistance. So
treatment guided by prior knowledge
Latent Tuberculosis Infection
positive tuberculin skin test for HIV infected
persons is >=5 mm
 Prevalence of (+) test decrease with decreasing
CD4 T-cell counts Why?
 Persons with low CD4 T lymphocyte count should
have periodic X ray chest done esp. in high risk
group


HIV-infected individuals with latent TB infection
have an extraordinarily high rate of progression to
active tuberculosis compared to HIV-uninfected
persons

Treatment of LTBI very effective in preventing
persons infected with M tuberculosis from
developing active disease

Annual screening of all HIV-infected persons for
LTBI, and treatment of those coinfected with M
tuberculosis, is recommended
Option
Total
Duration
(months)
I
II
III
6
6
6
Initial Phase
Drugs
Interval and
Duration*
Continuation Phase
Drugs
INH
RIF
PZA
EMB (or SM)
(HRZEorS)
Daily for 8 weeks
INH
RIF
PZA
EMB (or SM)
(HRZEorS)
Daily for 2 weeks
INH
RIF
PZA
EMB (or SM)
(HRZEorS)
Thrice weekly for 26 weeks
then
Interval and
Duration #
INH
RIF
(HR)
Daily for 16 weeks
INH
RIF
Twice weekly for 18
weeks
Twice weekly for 6
week
or
Twice weekly for 16
weeks
Recommended regimen