TB and HIV

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Tuberculosis HIV A Bad Combination

• Julie Jarand MD FRCPC
• University of Calgary
• Division of Respiratory Medicine
• March 25, 2010

Presenter Notes
Thursday March 25, late morning probably around
1100am, the agenda is not finalized but plan for
30-45mins and I will let you know details when I
have them.  The topic is TB and HIV, we were
thinking about a case study to illustrate some of
the challenges in treating/managing a co-infected
case.  Dr. Cowie thought you could include
something on drug resistance thinking about our
recent PLC case and perhaps drawing on some of
your S. Africa experience as well.  The
conference is Alberta/Western Canada, attendance
is mostly nurses working in the community who may
see a few cases of TB each year, also ICP's,
OHN's, folks from Prov Lab, corrections, long
term care, a few GP's, etc. 

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Tuberculosis old news?

• Hershkovitz PLoS One 2008

Presenter Notes
MTB complex DNA from extinct bison dated 17,000
years before present

Rothschild Clin Inf Dis 2001



Skeletal remains show prehistoric humans (7000
BC) had TB (Hershkovitz)



1882 Robert Koch identified and described
tuberculosis bacillus (108 years ago)



March 24th world TB Day

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History

• TB
• 1839 Disease named Tuberculosis
• 1882 Koch discovers TB bacillus
• 1907 Mantoux test developed
• 1921 BCG vaccine 1st used in humans
• 1946 Streptomycin introduced
• 1950 PAS combined with SM
• 1952 INH developed
• 1967 Rifampin introduced

• HIV/AIDS
• 1981 AIDS 1st recognized
• 1983 HIV identified as cause of AIDS
• 1984 HIV antibody test developed for diagnosis
• 1986 1st ARV available
• 1996 HAART becomes available
• 2007 Wide range of different drugs available

Presenter Notes
26 year history of HIV/AIDS

158 year history of TB

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http//www.lung.ca/tb/images/full_archive/158_mort
_stats.gif

Presenter Notes
http//www.lung.ca/tb/images/full_archive/158_mort
_stats.gif



During the first half of the 20th Century, TB was
called "consumption" or "white plague", and it
was the number one killer of Canadians. The
historic menace of the "White Plague" continued
for so many centuries because people had a poor
understanding of the disease and poor medical
tools with which to fight it.

Canadian Lung Association www.lung.ca



SM 1946

PAS - para-aminosalycilic acid late 1940s

INH - 1952

Rif - 1967

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Two entities have compromised global progress of
TB control..

• Epidemic of HIV
• Progressive emergence of drug-resistance

Adapted from Paul Nunn, Global Task Force on XDR
TB, Geneva, 2006

Presenter Notes
Since mid-20th century significant worldwide
decline in incidence of TB following the
introduction of multidrug anti-tuberculous
therapy



Drug-resistant TB appeared shortly after the
introduction on SM in mid-1940s

Increasingly, DRTB has become an ominous problem
threatening to destabilize global TB control



Evolution of Drug resistance

6
TB HIV Objectives

• Epidemiology of the association
• Nature of the immune problem
• Clinical presentation of HIV-associated TB
• Role and Timing of Antiretroviral Therapy
• Complicating factors eg. IRIS, drug
  interactions, side effects
• Screening/Preventative therapy

7
TB HIV - The scope of the problem

• Estimated 1.4 million HIV positive TB patients
  globally (2008)
• Globally, TB is a most common cause of death in
  HIV infected patients
• 500,000 deaths due to HIV-associated TB (2008)
• HIV patients with latent tuberculosis infection
  are 20-30 times more likely to develop TB disease
  compared to those without HIV.

Presenter Notes
9.4 million new cases TB each year of which
approx 14 HIV infected



Then number of new cases of TB has tripled in
high HIV prevalence areas in the last two decades
but has since been declining

TB is the most common presenting illness among
pts living with HIV pts on ARVs

At least one-third of the 33.2 million people
living with HIV worldwide are infected with TB
and are 20-30 times more likely to develop TB
than those without HIV and one in four people
with HIV die due to TB.



People with HIV need early diagnosis and
treatment of HIV.

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Cape Times October 2008
9
National data

• The level of TB-HIV coinfection in Canada is
  uncertain.
• Special Report by Canadian Tuberculosis Committee
  (April 15, 2007)

Figure 1. Proportion of TB cases reported in
Canada for which HIV status was known 1997-2004

Presenter Notes
Canadian numbers for TB from PHAC TB 2008
pre-release, see website --http//www.phac-aspc.gc
.ca/tbpc-latb/pubs/tbcan08pre/index-eng.php
(doesnt report HIV co-infection rate)

Canadian HIV epi report from PHAC (2007)
approx 58,000 people living with HIV in Canada at
end of 2005. Approx 2300-4500 new cases in 2005

HIV surveillance report (Canada 2008)
http//www.phac-aspc.gc.ca/aids-sida/publication/s
urvreport/2008/dec/index-eng.php

Special Report by Canadian Tuberculosis
Committee- Tuberculosis and HIV co-infection in
Canada (April 15, 2007)

Estimates range from 1.6 to 19.

http//198.103.98.193/publicat/ccdr-rmtc/07vol33/d
r3308a-eng.php

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Alberta experience

• 2003-2008 - overall HIV co-infection rate was
  6.3
• Universal opt out HIV testing

11
The prevalence of HIV in TB patients in Alberta
by age, sex and population group, 2003-2008
15-34 35-64
Male Female
CBO CBA FBO FBSSA
Age Sex Population Group
CBO Canadian-born other FBO foreign-born
other CBA Canadian-born Aboriginal FBSSA
Foreign-born sub-Sahara Africa

Presenter Notes
Taken from Richard Longs presentation at
Tuberculosis Control Committee of Alberta meeting
in Oct 2009

Alberta 2003-2008 The overall HIV co-infection
rate was 6.3 the HIV co-infection rate in the
age group 15-64 years, where all of the HIV
co-infected patients were situated, was 8.5.



It is very unlikely that these proportions will
change in 2009. As of weeks end, October 25, we
have had 9 HIV co-infected patients in 2009 6
foreign-born (5 from SSA) and 3 CBA all in the
age group 15-64 yrs. 1 co-infected patient is a
child (an international adoptee and the first
child-aged TB patient in Alberta that is
co-infected).



First, it was of immediate benefit to the
patients, many of whom were not known to be
HIV-infected and had low CD4 counts.

Second, it reinforced the need for targeted
tuberculosis preventive therapy in HIV-TB
co-infected persons.

Third, it identified the need for greater STI
prevention and control particularly in Aboriginal
peoples and greater emphasis on HIV and AIDS
prevention activity in both Aboriginal peoples
and immigrants to Canada from sub-Saharan Africa.


Fourth, it added weight to the argument that all
immigrants and refugees with HIV infection ought
to be referred for medical surveillance for both
HIV and TB, as a condition of entry.

Fifth, it underscores the need for a much greater
provincial/territorial and national response to
what are unacceptably high rates of TB and HIV in
Aboriginal peoples and the need for a strong and
sustained international response to TB and HIV in
developing countries, particularly those of
sub-Saharan Africa.



12
Why is HIV TB such a bad combination?

• HIV attacks cell-mediated immunity the most
  important part of immune system in mediating an
  effective response to TB
• Significantly affects immune systems ability to
  contain latent TB infection but also to prevent
  new infection

Presenter Notes
Immune response to TB contributes to both
pathology and protection

Active TB may enhance the progression of HIV
disease

MTb increases HIV replication in vitro

Degree of immunosuppression is the most important
predictor of survival in HIV patients with TB

Less likely to see granulomas

13
HIV negative
HIV positive

Presenter Notes
Immune response is also reflected in TST
increase likelihood of false negative results

Active TB may enhance the progression of HIV
disease

MTb increases HIV replication in vitro

14
Case Study

• 34 yo male, previously well
• 1 month history abdominal pain, watery diarrhea x
  1 week
• 3 month history decreased appetite, 8 kg weight
  loss, intermittent night sweats and possible
  fevers
• No cough, hemoptysis, shortness of breath

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Case study (2)

• Born in Guadalajara, Mexico
• Came to Canada 2 years ago on work visa
• No known history of TB, TB contacts, TB treatment
• Lifelong non-smoker, no recreational drug use,
  history of unprotected sex
• Physical exam generally unwell, not toxic,
  thin, HR 105, vitals otherwise stable, mild RUQ
  tenderness

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Case Study (3) - investigations

• Rapid HIV test positive (CD4 count 62)
• Lymph node biopsy multiple AFB seen on
  histopathology, culture not sent
• Started on empiric TB and MAC Rx (INH, Rif, PZA,
  EMB, azithromycin and Vitamin B6)
• Stool, blood cultures pending, unable to induce
  sputum

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Case study contd

• Bronchoscopy BAL culture positive, PCR positive
  for MTB complex
• Stool cultures also positive

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Questions?

• Is this typical for HIV-associated TB?
• When should ART start?
• What is this patients prognosis?
• How long should we treat TB in this case?
• Are there any special considerations in this case?

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Clinical presentation of TB in HIV patients

• Extrapulmonary disease is more common
• Lymph nodes most common site
• May have atypical or non-specific symptoms
• CXR less likely upper lobe, cavitary disease
• May have normal CXR
• Most commonly smear negative

Presenter Notes
Particularly prior to starting LTBI need to be
rigorous in excluding active dz (even if atypical
findings)

Symptoms may be atypical, non-specific and
overlap with symptoms of HIV and/or other OIs

Lymph node is most common site but pleural,
pericardial, TB meningitis and disseminated dz is
more common in HIV infected pts compared with HIV
negative patients

Amount of radiologic abnormality may depend on
degree of immunosuppression

May have positive blood cultures

May not see granulomas

Pathology is a bit different as there is poor
granuloma formation and minimal cellular
reaction, severe necrosis and can have abundant
AFB



Clinical, radiologic and microbiologic dx may be
altered in advanced HIV

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Treatment of TB in HIV patients

• TB cure rates are similar in HIV infected and
  uninfected patients
• Some studies show increased recurrence in HIV
  patients
• Ensure DOT, supportive care
• May consider extending treatment in patients slow
  to respond and cavitation

Presenter Notes
Caveat to the first statement is this is assuming
patients received good treatment eg. Good
compliance/DOT, tolerated meds well, drugs didnt
have to be stopped due to side effects
/-malaborption (as in some studies with increase
relapse rates this was the case)

First statement assumes drug susceptible organism
and ensured compliance



Rates of re-infection higher in HIV patients in
high-prevalence areas



May consider extending treatment patients slow to
respond and cavitation









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Drug resistance

• Rifampin monoresistance is more common in HIV
  patients typically acquired resistance
• At least three times weekly therapy (especially
  if CD4 count lt100 x 106/L)
• Is HIV an independent risk factor for drug
  resistant TB?

Presenter Notes
HIV not been shown to be a risk factor for DR-TB
infection but, HIV increases the risk of disease
progression after infection



Data limited from WHO Drug resistance
surveillance (up until 2007) only 7 countries
report (2 with best data from former Soviet
Union)

supporting evidence suggests that association
between HIV and MDRTB/XDRTB may be more closely
related to environmental factors such as
transmission in congregate settings rather than
biologic factors. Though, this requires further
investigation, it indicates that improving
infection control in congregate settings (eg.
Health care facilities and prisons may be one of
the most critical components in addressing dual
infection. (taken from WHO 4th global drug
surveillance report)



Increased risk of rif resistance with lower CD4
count (eg lt100) therefore at least 3X weekly

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Lancet 20063681575-80

• 52 of 53 XDR-TB patients died with median
  survival of 16 days from time of diagnosis (date
  of sputum collection)
• 44 patients tested for HIV were positive
• 2/3 of patients recently hospitalized

Presenter Notes
Data limited from WHO Drug resistance
surveillance (up until 2007) only 7 countries
report (2 with best data from former Soviet
Union)

supporting evidence suggests that association
between HIV and MDRTB/XDRTB may be more closely
related to environmental factors such as
transmission in congregate settings rather than
biologic factors. Though, this requires further
investigation, it indicates that improving
infection control in congregate settings (eg.
Health care facilities and prisons may be one of
the most critical components in addressing dual
infection. (taken from WHO 4th global drug
surveillance report)

27
Nosocomial Transmission Infection Control

Presenter Notes
Refer to our study looking at nosocomial
transmission in XDR wards



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What is my prognosis, doc?

• BAD NEWS
• Mortality of HIV-associated TB 13-44
• Iseman 2001
• Mortality increases with lower CD4 counts

• GOOD NEWS
• ART reduce mortality rates in patients with HIV
  associated TB 64-95
• Lawn et al Clin Chest Med 2009

Presenter Notes
Mortality of disseminated TB is 25-30 Lancet ID
2005

Mortality of HIV infected with TB is higher than
HIV infected pts without TB (even at same CD4
count)

Risk factors associated without poor survival
low CD4 count, no DOT, presence of MDRTB, history
of IV drug use, extrapulmonary TB (?2ary to delay
in dx)- CID 1999 Schluger



Recent study NEJM Feb 2010





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Timing of ART

Presenter Notes
NEJM Feb 2010 open label RCT mid 2005-2008
HIV (CD4lt500), smear TB (total N642) (429
grp 1 2 combined, 213 grp 3) grp 1- ARVs
started within 4 weeks of start of TB Tx (early
integrated), grp 2 within 4 weeks of completion
of intensive phase (late-integrated), grp 3
within 4 weeks of completion of TB rx (sequential
therapy)

Primary end point death from any cause. Trial
stopped early (2 months after enrollment closed,
supposed to f/u for 24 months) given increased
deaths in sequential arm (DSM comm recommended
starting these pts are ARVs right away, no
changes to the other groups)

Median duration of f/u 12.1 months

IRIS 12.4 (integrated) vs. 3.8 (sequential)



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Immune Reconstitution Syndrome

• Recovering immune system drives exaggerated
  inflammation directed at opportunistic pathogens
• Occurs in 8-43 of patients starting ART
• Median interval is 2-4 weeks
• Most commonly recurrent symptoms, fever, lymph
  node enlargement, pleural effusions, abdominal
  symptoms.
• Risk factors for IRIS disseminated TB, low CD4
  count, shorter interval from TB treatment to ART

Presenter Notes
Immune response to TB contributes to both
pathology and protection

Meintjes Clin Chest Med 2009

Need to exclude other diagnoses (in particular
OIs)

Cases can occur after a few days or, rarely,
months after ART started

Median duration of symptoms is 2-3 months

Abdominal manifestations also frequent but not
widely reported hepatic and splenic
involvement, peritonitis, ascites, node
enlargement

Hepatic involvement in 21-56 can be difficult to
distinguish from drug-induced hepatitis

Mortality is rare but morbidity can be
significant

Risk factors for IRIS disseminated TB, low CD4
count, shorter interval from TB treatment to ART

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IRIS

• Start ART 2 weeks - 2 months after starting TB
  treatment (in pts with low CD4 counts)
• Management
• Supportive/symptomatic
• Consider Steroids
• Continue ART unless life-threatening IRIS

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Case study 34 yo male

• Started ART 2 months after TB treatment
  (Abacavir, Lamivudine, Efavirenz)
• Approximately 1 week later, developed fever,
  abdominal pain and diarrhea
• Elevated cholestatic liver enzymes
• Dx with IRIS treated with prednisone 1mg/kg,
  ART and TB Rx (HR) continued

Presenter Notes
Readmitted to hospital

Extensive work up did not identify any new
infections/diagnoses

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Special considerations

• Drug-drug interactions (TB meds with ART)
• Rifampin/rifabutin
• www.cdc.gov/tb/publications/guidelines/TB_HIV_Drug
  s/default.htm
• Adverse effects are common
• Higher incidence of neuropathy
• Malabsorption

Presenter Notes
To date, not clear that HIV itself is a risk
factor for MDR or XDR Tb

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Screening and Prevention

• ART reduces risk of TB by approx 70 (range
  54-92)
• Absolute reduction in TB rates greatest in most
  advanced HIV disease
• Even HIV patients with CD4gt500 have a two fold
  higher risk of TB

Presenter Notes
ART reduces risk of TB by approx 70 (range
54-92) (Lawn et al Clin Chest Med 2009)

This protective effect is seen in both high (eg.
US) and low income (eg. South Africa) countries

Benefits are seen across a broad range of degrees
of baseline immunodeficiency and clinical stage
of disease, although absolute reduction in TB
rates is greatest in those with most advanced HIV
disease

Even HIV pts with CD4gt500 have two fold higher
risk of TB compared with non-HIV subjects in same
community (South Africa)



How to improve role of ART

Start ART earlier (eg. Higher CD4 count),
currently many patients already have TB or are at
high risk of TB when they start ART (eg. South
Africa WHO stage 4 dz or CD4 lt200)



Treatment of LTBI in TST HIV patients
significantly reduces risk of developing active
TB but reduction in mortality has not clearly
been shown.

-consideration should be given to LTBI treatment
in TST negative HIV infected individuals likely
to be at increased risk of LTBI (eg. High
epidemiologic risk or chest radiographic features
suggest of past TB exposure) who are
immunosuppressed to a degree likely to result in
false negative TST (Level III evidence)
Canadian TB guidelines

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Screening and Prevention

• All TB patients should have HIV testing
• All HIV patients should have screening for active
  and latent TB
• Annual risk of TB reactivation is up to 10
• TST (positive 5 mm) offer chemoprophylaxis
  with INH x 9 months
• Consider IGRA if TST negative
• October 2008

Presenter Notes
Treatment of LTBI in TST HIV patients
significantly reduces risk of developing active
TB

Can consider DOT twice weekly INH



To date, the goal of universal HIV testing of TB
patients in Canada remains elusive (27.2 of TB
patients were reported as HIV tested in 2006)
despite the existence of two national advisories,
one in 1992 and another in 2002, recommending
universal HIV testing of TB patients. (Richard
Long paper)

An Advisory Committee Statement (ACS)Canadian
Tuberculosis Committee (CTC)

In an immunocompromised person (adult or child),
the TST should be the initial test used to detect
LTBI. If the TST is positive, the person should
be considered to have LTBI.

However, in light of the known problem with
false-negative TST results in immunocompromised
populations, a clinician still concerned about
the possibility of LTBI in an immunocompromised
person with a negative initial TST result may
perform an IGRA test. If the IGRA result is
positive, the person might be considered to have
LTBI. If the IGRA result is indeterminate, the
test should be repeated to rule out laboratory
error. If the repeat test is also indeterminate,
the clinician should suspect anergy and rely on
the persons history, clinical features, and any
other laboratory results to make a decision as to
the likelihood of LTBI. Although both IGRAs may
be used as described above, there is evidence
that the T-SPOT.TB assay may be more sensitive
than the QFT-GIT assay in active TB, and this
characteristic might be especially relevant in
immunocompromised populations. While the approach
of accepting either test result (TST or IGRA) as
positive will improve the sensitivity of
detecting LTBI in immunocompromised populations,
there are no data supporting the efficacy of
preventive therapy in TST-negative but
IGRA-positive individuals. Thus the clinician
must weigh the potential benefit of detecting
more persons with positive test results against
the lack of evidence for the benefit of
preventive therapy in such persons.

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Summary

• Screen TB patients for HIV and screen HIV
  patients for TB
• Remember clinical presentation of TB often
  atypical in HIV patients
• ART reduces risk of TB and TB related mortality
  significantly
• Collaborative approach to TB/HIV care

Presenter Notes
Clinical presentation may be atypical

Get experts involved as it can be complicated

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Thank you!
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