Title: Diagnostic and therapeutic dilemmas in HIV care: Immune reconstitution inflammatory syndrome
1Diagnostic and therapeutic dilemmasin HIV care
Immune reconstitution inflammatory syndrome
- Papa Salif Sow MD, MSc
- Department of Infectious Diseases Dakar
University Teaching Hospital, Dakar Senegal
2Introduction
- 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
3Definition 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
4Introduction
- 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
5Introduction (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
6Other terms for Immune Reconstitution
Inflammatory Syndrome (IRIS)
- Immune Reconstitution Syndrome (IRS)
- Immune Restoration Disease (IRD)
- Immune Reconstitution Phenomena
- Paradoxical Reaction (TB)
7Differential 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
8Overview
- Pathogenesis
- Incidence of IRIS
- Clinical Manifestations
- Management
- Conclusions Perspectives
9Pathogenesis 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
10Pathogenesis 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
11Pathophysiology
- Patient with HIV infection
- Antiretroviral Treatment
- Immune Reconstitution Syndrome
- Inflammatory Response
Progression of previous lesions
Appearance of new lesions
12Incidence of IRIS
13Immune 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)
14Immune 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 16Incidence 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
17Incidence 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
18Incidence 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
19Risk 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
20Median 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
21IRIS 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
22TB 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
23TB IRIS
24TB IRIS
25- AIDS 2005, 19 1201 - 1206
26IRIS 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
27IRIS 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
28IRIS 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 30The 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
32IRIS 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
33IRIS 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 35IRIS 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
36IRIS and Herpes lesions
37IRIS 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)
38CMV IRIS
CMV retinitis
39Summary timeframe IRIS
40Conclusion
- 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