IRIS

Imunologi dan clinical aspek

CST Team
 Whole blood

Red cells White cells Platelets

Lymphocytes Other white cells

B cells T cells NK cells

CD4 T cells CD8 T cells

 Karakteristik CD4+
 Konduktor dari immune orkestra
 Berproliferasi sbg respon terhadap
antigen yg dipresentasikan oleh APC
berasosiasi dengan MHC class II
 Menentuka tipe dari immune respon
 Secara phenotype di karakteristik menjadi
“naïve” dan “memory“ – Berdasarkan CD
45
◦ CD 45 RO – Memory
◦ CD45 RA - naive
 Natural History
CD4+ T-Lymphocyte count (cells/mm3)

Primary
1,200 Death
infection ± Acute HIV syndrome

HIV RNA copies per ml Plasma

1,100 Wide dissemination of virus
1,000 Seeding of Lymphoid Organs
Opportunistic
900 disease
Clinical latency
800
700
600 Constitutional
500 symptoms
400
300
200
100
0
0 3 6 9 12 1 2 3 4 5 6 7 8 9 10 11+
Weeks Years
Modified from Fauci et al. Ann Int Med 1995;124:654
Perubahan pada CD4 naïve dan memory pada
infeksi HIV
70

60
Percent of CD4+ Cells

50

40

30

20 Naïve CD4 cells

10 Memory CD4 cells

700 600 500 400 300 200 100 0

Mean CD4+ Cell Count (cells/µl)
Connors. Nat Med 1997;3(5):533-40
 Immune Rekonstitusi pada ARV
 Fase ke 1 - ↑ cepat # CD 4 ke sirkulasi
perifer dari jaringan limph
› Redistribusi CD 4 yg terjebak dalam proses
inflamasi semalah infeksi HIV
› Terjadi pada 8 – 12 mgg pertama
› Peningkatan CD4 berbanding lurus dengan
penurunan viral load
 Fase ke 2 – ↑ lambat # CD 4
› Didominasi oleh “naïve”CD4 diikuti ↑CD8 naïve
› #CD 4 “memory” tetap dan CD 8 “memory” ↓
› Peningkatan secara lambat terjadi pada 2 thn
pertama pengobatan
 Definisi
 a paradoxical inflammatory reaction
against a foreign antigen (alive or dead) in
patients who have started antiretroviral
therapy and who have undergone a
reconstitution of their immune responses
against this antigen’
 Insiden
 Data Pasti tidak diketahui – Definisi
 Rata – rata 17 – 32%
 Data dari Indonesia - ?? RSPI melaporkan
…
 Faktor klinis yg berhubungan
dengan timbulnya IRIS
 Laki – laki
 Usia muda
 Baseline CD4 yg rendah sebelum dimulai
ARV
 Viral load yg tinggi pada saat dimulai ARV
 Penurunan yg cepat dari viral load setelah
diberikan ARV
 ARV diberikan bersamaan diagnosis OI
 Jarak antara pengobatan OI dan ARV terlalu
dekat
Faktor Resiko
 Kriteria Diagnosis
 Diagnosis ditegakkan dengan 2 kriteria major ( A+B) atau 1 kriteria Major (
A)+ 2 kriteria minor

 Major criteria

 (A) Atypical presentation of opportunistic infections or tumors in patients

responding to ART
 • Localized disease
 • Exaggerated inflammatory reaction
 • Atypical inflammatory response in affected tissues
 • Progressive organ dysfunction or enlargement of pre-existing lesions
after definite clinical improvement with pathogen specific
 therapy before the initiation of ART and exclusion of treatment toxicity
and new alternative diagnoses

 (B) Decrease in plasma HIV RNA concentration by more than 1 log10

copies per mL
 Minor criteria
 • Increase in blood CD4 T-cell count after
starting ART
 • Increase in an immune response specific
to the relevant pathogen— eg, delayed-type
hypersensitivity skin test response to
 mycobacterial antigens
 • Spontaneous resolution of disease
without specific antimicrobial therapy or
tumor chemotherapy with continuation of
ART
 General IRIS case definition 2 (Shelburne et al, 2006)13
 Criteria for IRIS diagnosis include:
 • HIV-infected patient
 • Receiving effective ART as evidenced by a decrease in HIV-
1 RNA concentration from baseline or an increase in CD4+ T
cells from
 baseline (may lag behind HIV-1 RNA decrease)
 • Clinical symptoms consistent with inflammatory process
 • Clinical course not consistent with expected course of
previously diagnosed opportunistic infection, expected
course of newly
 diagnosed opportunistic infection, or drug toxicity
Spektrum Iris
 TB - IRIS
 Restoration of mantoux positivity
 Manifestasi klinis:
◦ Worsening fever
◦ Lymphadenopathy
◦ Pulmonary infiltrates
◦ Focal cerebritis
◦ Pleural effusions
◦ Organomegaly
◦ Ascities
◦ hypercalcaemia
 Insiden TB- IRIS
Europe and USA
◦ Narita et al 36% (Miami, 1998)
◦ Wendel et al 11% (Baltimore 2001)
◦ Breen et al 29% (London, 2004)
◦ Breton et al 43% (Paris, 2004)
Africa
› Breton et al: 41%
› No cases in TB/DOT study in South Africa (20
patients only)
India
› Kumarasamy et al: IRIS of 15.2 cases per 100
patient-years
› Patel et al: TB IRIS more often in patients with active
TB at the start of HAART than in those without
active TB at the start of HAART (11 [8.73] vs. 3
[2.32%], respectively; p = 0.0489).
Indonesia???
 Faktor Resiko untuk TB/IRIS
 Memulai ARV dalam 6 mgg dari
pengobatan TB
 Disseminated, extra-pulmonary disease
 CD4 yg rendah
 Peningkatan CD4 %
 viral load yg turun dengan cepat
 Bakteriemia?
 Tipe TB-IRIS
 Tidak diketahui mempunyai TB pada
waktu ARV
 Pasien sedang dalam pengobatan TB pada
waktu dimulai atau sebelum ARV
Waktu Terjadinya
◦ Rata2 15 hari setelah mulai ART

◦ Bisa sampai berbulan-bulan

◦ Syndrome lasts for 10-40+ days

 HIV, TB
R para-tracheal
nodes

Stridor -
2 months
after ARV
and DOT
for TB

Clinical Radiology
59, 6 , 2004, Pages 505-513
 Dicurigai TB IRIS – Pasien TB yg
setelah dimulai ARV timbul tanda
 New persistent fevers (temperature >38.6°C)
which last for more than 1 week without an
identifiable source (e.g., urine and sputa testing,
and other procedures when clinically indicated)
or reason (e.g. an allergic reaction)

 or marked worsening or emergence of

intrathoracic lymphadenopathy, pulmonary
infiltrates

 or worsening or emergence of cervical

adenopathies/abscesses, or worsening of other
tuberculous lesions or manifestations, such as
cutaneous peritoneal or central nervous system
(CNS) inflammatory pathology.
 Dicurigai IRIS – Pasien setelah
dimulai ARV timbul TB dengan tanda
 TB miliar dengan pembesaran nodul
 Cold Abses
 Adenopati luas
 Adanya cavitas
 “Confirmed” TB IRIS
Sama dengan definisi “ suspected TB IRIS”
tetapi

 MDR disingkirkan
dan
 Respon virologis yg baik dengan ARV
 Pengobatan
 Pengobatan TB dilanjutkan
 Exclude treatment failure

◦ Ensure adequate treatment

◦ Ensure adherence to ATT
◦ Consider drug resistance
 Drainage
 Penggunaan NSAID/steroid mungkin menolong
 ARV dilanjutkan
 Pertimbangkan utk stop ARV pada kasus life threatening?