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PATOFISIOLOGI HIV

Evy Yunihastuti
Divisi Alergi Imunologi Klinik Departemen Ilmu Penyakit Dalam
FKUI/RSCM
Pokdisus AIDS FKUI/Unit Pelayanan Terpadu HIV RSCM

HIV preferentially infect CD4+ T cells

Spread of HIV in Host Tissues

Staging of Acute and Early HIV-1 Infection

Modified from Cohen et al NEJM 2011; 364:20 p 1943-54

HIV Testing Assays and Window Periods

Branson and Steckler J. Inf. Dis. 2012; 205:521-524

Pathogenesis and Natural Course of the


Disease

10

HIV RNA Levels Predict Progression to AIDS

CD4 dan infeksi oportunistik

Infeksi oportunistik
} Tuberkulosis
} CD4 < 200: gambaran klinis

dan radiologis tidak khas,


ekstraparu
} CD4 > 200: seperti TB lain

Infeksi oportunistik
} Kandidiasis orofaring dan

kandidiasis esofagus

} Herpes zoster

Infeksi oportunistik
} Ensefalitis toksoplasma

} Meningitis kriptokokus

Infeksi oportunistik
} Histoplasma

} Retinitis

OD

CMV

Kanker terkait HIV


} Kanker kelenjar getah

bening
} Kanker leher rahim
} Sarkoma Kaposi

Cancer related virus

Gangguan organ/sistem terkait HIV


} Anemia, leukopenia, trombositopenia (darah)
} Kardiomiopati HIV (jantung)
} Nefropati HIV (ginjal)
} Neuropati HIV (saraf perifer)
} HIV-associated dementia (pikun)
} dll

Hasil pengobatan
Perbaikan klinis nyata
Bisa produktif
Setelah 6 bulan terapi:
>90% mencapai kadar virus
undetectable: < 400 kopi/cc darah)

Efektivitas
" Respons komplit dan inkomplit 92%
" Gagal terapi 8% (Amir Fauzan, 2005)

Survival 1 tahun
v66% tetap hidup dalam 1 tahun
vSebagian besar meninggal pada 3 bulan
pertama pengobatan (Indah Mahdi, 2005)

Pentingnya ADHERENS (tekun berobat)


90

% pasien dengan
keberhasilan virologik

80
70
60
50
40
30
20
10
0
95

90-95

80-90

70-80

<70

% Kepatuhan
Patterson, et al. Ann Intern Med. 2000;133:21-30.

Which Organ Contains The Most T Cells?

1.The Lymph Nodes


2. The Gastrointestinal Tract
3.The Blood
4.The Spleen

Where does CD4+ T cell depletion occur?

Substantial depletion of mucosal CD4 T cells in acute SIV


infection
Mattapallil JJ, et al. Nature. 2005;434:1093-1097.

Profound Depletion of Mucosal Barrier


HIV

Acute HIV+!

There is a marked reduction in mucosal CD4 cells T


cells, DCs, and macrophages
Brenchley JM, et al. J Exp Med. 2004;200:749-759.

A model of HIV pathogenesis


HIV-1 infection and replication
Main target CCR5+ activated CD4+ T cell

Massive CD4+ T cell depletion


Anti-HIV immune
response

In particular mucosal CD4+ T cell

Production of HIV
proteins
Gp120, nef

Cellular and humoral

Bacterial
Translocation
Incl. TLR ligand

Viral reactivation
In particular CMV

Systemic immune activation


Adaptive and innate

Systemic immune activation


Adaptive and innate

Sustained T-cell
apoptosis
Turn over and senescence

Secretion of proinflammatory
cytokines
e.g. IL-6, TNF, IL-1

Homeostatic mechanism
Cellular renewal
hematopoesis

HIV
replication

Exhaustion of immune
response
Decline of regenerative capacity
loss of effective anti-HIV immunity

= Immunosenescence?

Damage
To
Lymphoid
tissue

Inflammation-related
disorders
Osteoporosis
Atherosclerosis
Neurocognity deterioration
Frailty

= inflammation-ageing?

Persistence of this process

=> Collapse of immune system / AIDS

Comorbidity in relation to age

Schouten J AIDS 2012

Non-AIDS cancers

Osteoporosis

CVD

Depression

Diabetes mellitus

Chronic liver disease

Frailty

COPD

Cognitive disorders

Chronic renal
disease

Recovery of Central Memory CD4 T Cells in Peyers Patches

Central memory CD4 T cells can recover in Peyers patches if


HAART is commenced in early infection

Virus persists in all patients on cART


Blood"

Tissue"
Cell associated HIV DNA"

HIV RNA

Cell associated HIV RNA"


Cell associated HIV DNA
Cell associated HIV RNA
Infectious virus (IUPM)
50
Plasma single copy assay
1

Years on cART

Chun et al., Nature 1997; 387: 183; Lewin et al., J Virol 1999; 73:6099; Palmer et al., Proc Natl Acad Sci U S A.
2008;105:3879; Chun et al., J Infect Dis 1997;195:1762; Yukl J Infect Dis 2010;

Sterilising cure: lessons learned

Hutter et al., N Engl J Med, 2009; 360:692

EFEKTIVITAS
PENULARAN

Per kejadian:
Hubungan seksual tak aman
0,1-1%
Tusukan jarum /perlukaan
0,3%
Percikan cairan tubuh pada
mukosa 0,09%
Transfusi darah > 90%
Dari ibu hamil ke bayi 35%

Padian et al. 2011. Lancet.

HPTN 052: randomized clinical trial of


immediate vs delayed ART in couples
Total HIV-1 Transmission Events: 39

Unlinked or TBD
Transmissions: 11

Linked
Transmissions: 28

Immediate
ART: 1

Delayed
ART: 27

One infection in immediate arm was soon after


HAART

96% reduction in HIV

p < 0.001
Cohen et al NEJM 2011.

transmission

ART only works when taken


In HPTN 052, viral suppression was near-universal, reflecting
intensive strategies, including quarterly monitoring and individual
counseling, to achieve near-perfect adherence

Immediate Arm
Delayed Arm (not on ART)
Delayed Arm (on ART)

Cohen et al NEJM 2011.

Penularan HIV dari ibu ke bayi


Tanpa intervensi: risiko total 35% (25-45%)
Risiko 7%
Selama kehamilan

Risiko 18%
melahirkan

Risiko 13%
Sesudah persalinan

Tanpa intervensi:
Risiko 7%

Risiko 18%

Intrauterin

intrapartum

Antiretrovirus
(ARV)

ARV
Operasi sesar

Risiko 13%
pascapersalinan

Bayi: ARV
Susu formula

Intervensi
Dapat menurunkan risiko penularan ke bayi menjadi <2%

A quick anatomy lesson

Keratin in Foreskin Tissue - IDL


Filaggrin
Involucrin
DAPI

GC Cianci
Dinh et al., PLosOne. 2012.

Male
circumcision
Auvert B, PloS Med 2005
Gray R, Lancet 2007
Bailey R, Lancet 2007

Treatment of
STIs
Grosskurth H, Lancet 2000

Microbicides
for women

Male & female condoms

Abdool Karim Q, Science 2010

HIV
Oral pre-exposure
PREVENTION
prophylaxis
combined
Grant R, NEJM 2010 (MSM)
Baeten J , NEJM 2012 (couples)
interventions
Thigpen, NEJM, 2012 (Heterosexuals)

Structural / legal

HIV Counselling
and Testing
Coates T, Lancet 2000

Post Exposure
prophylaxis (PEP)
Scheckter M, 2002

Treatment for
prevention
Donnell D, Lancet 2010
Cohen M, NEJM 2011

Behavioural
Intervention

Siapa yang sebaiknya diperiksa?


Gejala konstitusional:
} Demam berkepanjangan
} Fatig kronik
} Penurunan BB
} diare kronik
Gejala neurologis:
} Meningitis aseptik
}
Meningitis karena jamur, parasit
} Demensia tanpa sebab
Kelainan mulut:
} Kandidiasis oral
} Hairy leukoplakia
} Periodontitis agresif
} ulkus atau stomatitis aftosa
berat
berulang

Kelainan kulit:
Furunkulosis rekuren
Dermatitis seboroik berat
Eksaserbasi psoriasis
Herpes zoster
Sarkoma Kaposi

Siapa yang sebaiknya diperiksa?


Penyakit menular seksual:

Herpes simplex, Gonore

Klamidia, HPV

Sifilis, Kondiloma akuminata


Kelainan hematologi:

Anemia

Neutropenia

Trombositopenia

Limfopenia
Hepatitis:

Hepatitis C

Hepatitis B

Pneumonia:

Pneumonia rekuren

Pneumocystis pneumonia

Tuberkulosis
Infeksi jamur paru
Limfadenopati yang tak ditemukan
penyebabnya
Wanita hamil

The leaky cascade


We need
high testing
coverage
linkage to care
viral suppression
to reduce
infectiousness
and HIV incidence
at population
levels

Testing is the gateway to HIV


prevention and care

Acceptability of HIV
testing is high in large
scale campaigns and
Home based community
testing
Testing must be linked to
services & not simply
numbers
Requires systems for
effective linkage to
services

Navneet
Garg
| Global
Business
Manager
| Vestergaard
Frandsen outreach
In
Kenya:
41,040
people
tested
in 1 week
during a community

TERIMA KASIH
Pokdisus AIDS FKUI/RSCM
www.pokdisusaids.com
pokdisus@centrin.net.id
Telp. 021-3905250, 021-3162788