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Diagnostic and therapeutic dilemmas in HIV care: Immune reconstitution inflammatory syndrome

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Title: Diagnostic and therapeutic dilemmas in HIV care: Immune reconstitution inflammatory syndrome


1
Diagnostic and therapeutic dilemmasin HIV care
Immune reconstitution inflammatory syndrome
  • Papa Salif Sow MD, MSc
  • Department of Infectious Diseases Dakar
    University Teaching Hospital, Dakar Senegal

2
Introduction
  • Development of HAART has markedly improved the
    outlook for patients infected with HIV
  • Significant reduction of morbidity due to OI
  • Significant mortality rate
  • Improvement in quality of life
  • But since the use of HAART, the immune
    reconstitution inflammatory syndrome (IRIS) has
    been described which may occur in up to 40 of
    patients

3
Definition of IRIS
  • Previously latent or incubating diseases which
    become symptomatic or worse after the
    introduction of HAART
  • Paradoxical reaction worsening of symptoms of
    OIs which were already present (TB, MAC, CMV),
    shortly after starting HAART
  • In the presence of features consistent with an
    inflammatory process and a decreasing viral
    load and increasing CD4 cell count

4
Introduction
  • The clinical spectrum of IRIS is diverse and is
    associated with infection due to
  • Mycobacterium tuberculosis
  • Mycobacterium avium complex
  • Cryptococcus neoformans
  • Pneumocystis jirovecii
  • Hepatitis B and C
  • Herpes zoster
  • Kaposi sarcoma

5
Introduction (contd)
  • It is anticipated that IRIS will become more
    frequent as antiretroviral therapy becomes
    available in less developed countries where the
    underlying prevalence of M. tuberculosis, C.
    neoformans and hepatitis B is high and where
    patients initiating HAART are more likely to have
    advanced immunodeficiency

6
Other terms for Immune Reconstitution
Inflammatory Syndrome (IRIS)
  • Immune Reconstitution Syndrome (IRS)
  • Immune Restoration Disease (IRD)
  • Immune Reconstitution Phenomena
  • Paradoxical Reaction (TB)

7
Differential diagnosis of IRIS
  • ART toxicity e.g. NVP drug toxicity earlier
  • Noncompliance
  • Failure of treatment of OI (e.g. MDR, TB)
  • Failure of HAART late!
  • Previously present OI that were not diagnosed
    before starting HAART

8
Overview
  • Pathogenesis
  • Incidence of IRIS
  • Clinical Manifestations
  • Management
  • Conclusions Perspectives

9
Pathogenesis of IRIS
  • Poorly understood!
  • More frequent in patients with low CD4 at start
    (lt 100 cells/mm³)
  • Often associated with large fall in viral load
  • Different IRIS syndromes may involve different
    immunological mechanisms

10
Pathogenesis of IRIS
  • Pre-existing pathogen in the body
  • Initial lack of immune response due to immune
    deficiency
  • Immune recognition and response following HAART
  • Intense inflammation and clinical disease

11
Pathophysiology
  • Patient with HIV infection
  • Antiretroviral Treatment
  • Immune Reconstitution Syndrome
  • Inflammatory Response

Progression of previous lesions
Appearance of new lesions
12
Incidence of IRIS
13
Immune Reconstitution Syndrome
  • Narita, Am J Resp and Crit Care Med, 1998
  • 116 patients treated for TB
  • Group I 33 HIV patients also receiving HAART
  • Group II 55 HIV- patients
  • Group III 28 HIV patients without HAART
    (historical controls)

14
Immune Reconstitution Syndrome
  • Narita, Am J Resp and Crit Care Med, 1998
  • Incidence of IRS

50
40
36
30
Paradoxical reaction
20
7
10
3
0
HIV/HAART
HIV
HIV-
15
  • AIDS 2005, 19399-406

16
Incidence of IRIS (Shelburne et al.)
  • A retrospective chart review performed for 180
    HIV-infected patients who received HAART
  • 31.7 developed IRIS
  • More likely to be naive ARV patients
  • Initiated HAART nearer to the time of diagnosis
    of their OI
  • Have a more rapid initial fall in HIV-1 RNA level
    response to HAART
  • The majority of cases of IRIS occurred within the
    first 60 days of initiating HAART

17
Incidence of IRIS (Shelburne et al.)
  • The incidence of IRIS by infectious agents was
  • 13.6/100 patient-years HAART for M. tuberculosis
  • 15.1/100 patient-years HAART for M. avium complex
  • 15.7/100 patient-years HAART for C. neoformans

18
Incidence of TB IRIS
  • Transient exacerbation of clinical and
    radiological manifestations of TB
  • Paradoxical worsening of TB after HAART
  • Incidence TB IRIS
  • In Europe and USA between 11 and 45
  • In Paris (Breton et al.) TB IRIS incidence was
    43
  • In India 11/144 HIV/TB, 72 person-years
    developed IRIS within 6 months of initiating HAART

19
Risk factor for TB IRIS
  • Starting ARV within 6 weeks of starting TB
    treatment
  • Extrapulmonary or disseminated disease
  • Low CD4 lymphocyte count (lt 50 cells/mm3) at the
    start of ARV
  • Viral load gt 100,000 copies/mL

20
Median time to development of clinical TB IRIS
  • In the majority of patients TB IRIS occurs within
    the first 4-8 weeks of antiretroviral therapy
  • Kumarasamy et al. in India
  • 42 days (range 10-89 days)
  • Narita, Am J Resp and Crit Care Med, 1998
  • At onset of illness
  • Duration of TB therapy 109 days
  • Duration of HAART 15 days
  • CD4 92

21
IRIS and tuberculosis manifestations
  • Symptoms compatible with an inflammatory process
  • Fever
  • Dyspnoea
  • Worsening infiltrates or effusion, mediastinal
    peripheral lymphadenopathy, sometimes abscesses,
    intracranial tuberculomas
  • Restoration of cutaneous tuberculin reaction
  • AFB and culture may be negative
  • Appears in the first 1-6 weeks of HAART

22
TB IRIS clinical manifestations (Shelburne et
al.) AIDS 2005,19399-406
  • 26 cases patients with TB IRIS
  • 19 cases of worsening, cervical lymphadenitis
  • 5 cases of increasing pulmonary infiltrates
  • 4 cases of accumulating pleural effusions
  • 2 cases of prolonged fever

23
TB IRIS
24
TB IRIS
25
  • AIDS 2005, 19 1201 - 1206

26
IRIS and active TB
  • Objectives To assess whether HAART contributes
    to the presentation of active tuberculosis
  • Results 19 TB IRIS in a total of 111 patients
  • TB occurred in a median time of 41 days (7-109)
  • Median CD4 cell counts at baseline 87 in IRIS
    and 218 in patients without IRIS
  • Conclusions HAART may amplify the presentation
    of active TB. This has implications for
    antiretroviral programmes in countries with high
    TB rates and warrants prospective investigation
    of a larger cohort

27
IRIS and tuberculosis management
  • No guidelines available yet
  • Continue HAART switch regimen if needed
  • Start TB medication
  • Add steroids if needed especially in case of
    severe dyspnoea, TB meningitis
  • Furrer, Am J Med, 1999

28
IRIS and MAC
  • First 1-12 weeks after HAART initiation
  • Prolonged fever
  • Localized lymphadenitis usually cervical or
    abdominal
  • Hepatosplenomegaly
  • Lung infiltrates
  • Mycobacteraemia seldom occurs, sometimes culture
    of lymph nodes positive
  • Treat with ART, MAC treatment, steroids, drainage
    if needed

29
  • AIDS 2005, 191043-1049

30
The French Cryptococcosis Study Group
  • Retrospective multicentre study 1996-2000
  • Median time of occurrence 8 months (2-37)
  • 120 HIV-infected adult patients treated with
    HAART
  • 12 developed IRIS during the study period and
    experienced a first episode of culture-confirmed
    cryptococcosis
  • IRIS-related cryptococcosis was observed more
    frequently in severely immunocompromised patients

31
  • Journ of Infect. (2005) 51, 289-297

32
IRIS cryptococcosisReview from this group
  • 25 cases of IRIS Cryptococcus neoformans
  • Median time 7 months (range 2 weeks to 22
    months)
  • Median baseline CD4 count was 25 cells/mm3
  • Median baseline HIV viral load 439,053 copies/mL
  • IRIS presentation
  • lymphadenitis (n 14)
  • CNS IRIS (n 10)
  • meningitis (n 6)
  • mass lesions (n 4)
  • Pulmonary cavities (n 1)
  • Clinical manifestations resolution in 1 6
    months
  • 4 patients were given anti-inflammatory
    medications

33
IRIS and cryptococcal meningitis Key features
  • Usually 1 week 8 months after HAART
  • General manifestations
  • new headache, meningism, marked CSF leukocytosis
  • Unusual manifestations
  • lymphadenopathy, abscess, cavity pneumonia
  • Treatment HAART and antifungal therapy

34
  • CID 2004 39 1852 - 5

35
IRIS and Herpes Zoster
  • 1-4 months after HAART initiation
  • Typical and severe symptoms
  • Continue HAART
  • Give acyclovir in case of extensive or necrotic
    lesions, or in case of ophthalmic zoster
  • Be aware that AZT and acyclovir both induce bone
    marrow suppression

36
IRIS and Herpes lesions
37
IRIS and CMV
  • Ocular retinitis, uveitis, vitritis
  • Extra ocular diseases skin, colitis...
  • Patients do not always have past history of CMV
    infection
  • Usually occurs within 1-2 months after initiating
    HAART (uveitis till 2 years)

38
CMV IRIS
CMV retinitis
39
Summary timeframe IRIS
40
Conclusion
  • Patients need to be counselled at initiation of
    HAART about the potential development of IRIS
  • Patients at greatest risk for development of IRIS
    (CD4 lt 100 cells/mm3) should be screened to
    exclude an active or subclinical infection
  • Large prospective cohort studies and clinical
    trials are needed
  • Definition, risk factors, pathophysiology,
    immunological markers, or other simple laboratory
    parameters to diagnose IRIS
  • Guidelines for the management of IRIS are highly
    needed
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