PENANGANAN HIV - TB

Budi Enoch
Klinik Mawar
Singkawang
Epidemi Ganda

HIV TB
42 juta 2 milyar

WHO estimates, 2002 4

 DOTS
Epidemi TB
Epidemi HIV

5
HIV at risk TB infected

HIV + Active TB

HIV + with Active TB

6
 IO yang tersering (Thailand)

Tuberculosis

PCP

Cryptococcosis

Candidiasis, oesophageal

Pneumonia, recurrent

0 5000 10000 15000 20000 25000

Division Epidemiology, Department of Communicable Dise

IO terbanyak (Klinik Mawar, Juni 2006)

84,3%

72,5%
66,7%
60,8%

25,5%
19,6%
9,8%

OC WST GE PPE TBC ENC OTH

Penderita HIV (+) didiagnosa TB
tahun 2005 s/d Juli 2008

14

10
9
8

2005 2006 2007 2008

Penderita TB yang didiagnosa HIV (+)
tahun 2005 s/d Juli 2008

16

11
10

2005 2006 2007 2008

 Pulmonary Diseases in
AIDS
 Respiratory symptoms are a frequent
complaint in HIV-infected individuals.
 Spectrum of pulmonary diseases
includes both HIV and non-HIV-related
conditions.
 HIV-associated pulmonary conditions
include both OIs and neoplasms, each of
which has a characteristic clinical and
radiographic presentation.
 Because of considerable variation and
overlap in the presentation, no
pathognomonic or specific findings for a
particular disease.
 Definitive microbiologic or pathologic
diagnosis is preferable to empiric
therapy.
 OIs and neoplasms may be limited to
the lungs or pulmonary involvement may
be only one site of multi-organ disease.
CD4 cell count range for selected HIV-related
and non-HIV-related pulmonary diseases
Any CD4 CD4 < 500
- bacterial pneumonia - Bacterial pneumonia
- tuberculosis (recurrent)
- NHL - pulmonary mycobacterial
- bronchogenic carcinoma pneumonia (TB and NTM)
- pulmonary embolism

CD4 < 200

- PCP
- Cryptococcal pneumonia
- bacterial pneumonia
- disseminated or extrapulmonary TB
CD4 cell count range for selected HIV-
related and non-HIV-related pulmonary
diseases (cont’)
CD4 < 100 CD4 < 50
- pulmonary KS - diss. Histoplasmosis
- bacterial pneumonia - CMV pneumonitis
- toxoplasma pneumonitis - diss. MAC
- diss. TB
- diss. NTM
 TB - HIV AIDS

 Infeksi HIV dan menurunnya CD4

 Menurunkan kemampuan sistem
kekebalan tubuh untuk mencegah TB
 ODHA punya risiko 10 X untuk TB
 TB Paru adalah IO yang sering
ditemukan pada ODHA
 Manifestasi TB pada ODHA tergantung
derajad supresinya
Penderita HIV yang didiagnosa TB
Tahun 2005 s/d 2010

Jumlah = 54 orang
Penderita TB yang didiagnosa HIV
Tahun 2005 s/d 2010

Jumlah = 52 orang
 HIV/TB interaction

 Effect of HIV on TB Effect of TB on HIV

– HIV is high risk of
 HIV disease
developing active TB
progression
– Higher rates of
 reactivation disease
– 7-10% per year vs
10% lifetime risk Other OIs
HIV negative
 acute disease
– 50% HIV pos vs 5-
10% HIV neg lifelong
risk
morbidity,
skin test (PPD) anergy

mortality
 extrapulmonary TB
 Effect of CD4 count on risk of TB
among HIV-infected people
Incidence of TB (per 100 pyrs)
20
CD4 count
>350 200-350 <200
15

10

0
Italy US South Africa
Antonucci JAMA 1995;274:143; Markowitz Ann Int Med 1997;126:123;
Badri Lancet 2002;359:2059 Modified from A. Pozniak
 Natural History of TB Infection

Infection

10% disease
Few will not per year
develop disease
Natural History of TB Disease
If no treatment given

Death Natural Chronic

Cure
HIV ( - ) 50% 25% 25%
HIV (+ ) 100% 0% 0%
 TB in non HIV or Early
Stages of HIV Infection
● Typical of TB in immune competent
persons
– Usually localized to lung
– Usually upper lobes of lung
– Often with cavitations on chest
radiograph
– Usually AFB sputum smear positive
 TB in Later Stages of HIV
Infection
● Clinical
more extra pulmonary TB (limphadenopathy)
alone or in combination with pulmonary
● Microscopy in pulmonary disease
often AFB sputum smear negative
● Chest radiograph in pulmonary disease
mid or lower lobe or hilar (area around heart
shadow) involvement
 Correlation Between Extent of HIV-Induced Immuno-
Suppression and Clinical Manifestation of Tuberculosis
Median CD4 cell count / mm3 500 Pulmonary tuberculosis

400
Lymphatic, serous tuberculosis

300 Tuberculous meningitis

200 Disseminated tuberculosis

100

0
Early - Duration of HIV infection - Late
De Cock KM, et al. J Am Med Assoc 1992;268:1581-7
 Correlation between CD4 counts and
Clinical Manifestation of Tuberculosis
500 -
Pulmonary TB
400 -
CD4 counts

300 - Lymphatic, serous TB

200 - TB Meningitis

100 -
Disseminated TB
0-
Duration of HIV Infection (yrs)
Effect of Stage of HIV Disease on
CXR Manifestations of TB

Early HIV disease Advanced HIV disease

● Upper lobe ● Lack of cavitation

predominance ● Hilar adenopathy
● Cavitation ● Lower and middle lobe
● Pleural disease infiltrates
● Pleural and pericardial
involvement
RADIOLOGI
ANAMNESIS

 Gejala utama adalah batuk batuk lebih

dari 3 minggu
 Gejala sistemik :
demam,lesu,anoreksia,berat badan
turun dan keringat malam
 Gejala respiratorik : banyak dahak ,
batuk darah atau ada darah di dahak,
nyeri dada dan sesak nafas
RIWAYAT PENYAKIT
 Pernah menderita TB atau kontak dengan
pasien TB
 Pengobatan dengan OAT : jenis obat,lama
pengobatan,hasil pengobatan
 Pernah ikut program DOTS TB
 Imunisasi BCG
 Riwayat drug abuser Narkoba
 Pada anak : panas > 2episode tanpa sebab
dan riwayat test tuberkulin positif
PEMERIKSAAN FISIK
 Keadaan umum,kesadaran,status
gizi,serta tinggi dan berat badan
 Sering pasien kurus tetapi ada
ditemukan pasien gemuk dengan TB
HIV
 Hasil pemeriksaan paru sangat
bergantung luas dan kelainan struktur
paru.
 Pada awal penyakit tidak ditemukan
kelainan
KELAINAN DI PARU
 Kelainan biasanya didapat di puncak paru
 Radiologis dapat ditemukan
atelektasis,infiltrat halus atau hilus menebal.
Kasus yang berat dengan penarikan
diafragma dan mediastinum
 Suara nafas : bronkial,amforik,atau suara
nafas melemah dan ronki basah
 Evaluasi gigi dan mulut apakah ada selaput
putih,ulkus,atau bercak warna merah
keunguan ( kandidiasis,sarkoma kaposi )
PEMERIKSAAN
PENUNJANG
 Bakteriologik
 Radiologik
 Pemeriksaan penunjang lainnya :
 Uji tuberkulin
 kultur/biakan bakteri
 Hitung limfosit T helper ( CD4 )
 Pemeriksaan histopatologi jaringan
 Polymerase Chain reaction (PCR),
Serologi TB
 AFB smear

AFB (shown in red) are tubercle bacilli

AFB SMEAR
TB EKSTRA PULMONAL

 Sering ditemukan : limfadenitis,efusi

pleura,perikarditis,TB milier,meningitis
TB
 Jika terdapat TB ekstra Pulmonal
harus dicari apakah ada TB paru
dengan pemeriksaan sputum BTA atau
foto toraks
LIMFADENITIS TB
 Terdapat satu benjolan atau lebih umumnya
ditemukan di leher (paket)
 Pada awalnya tidak di dapat nyeri tekan dan bisa
menjadi abses
 Kadang disertai demam,keringat malam,dan nafsu
makan menurun
 Pembesaran KGB oleh HIV disebut persistent
generalized lymphadenopathy (PGL), toksoplasma,
atau infeksi banal
 Pembesaran KGB ditemukan pada limfoma dan
metastasis karsinoma
 Hampir 50% penderita HIV menderita PGL
Persistent Generalized
Lymphadenopathy (PGL)
 Pembesaran KGB selain di inguinal di 2 tempat atau
lebih dengan diameter > 1 cm selama 3 bulan atau
lebih
 Pembesaran tidak sakit,simetris dan sering terjadi
pada KGB servikal posterior dan epitrokhlear
 PGL adalah diagnosis klinis pada ODHA
 Pemeriksaan lebih lanjut dilaksanakan bila diameter
> 4 cm atau membesar dengan
cepat,asimetris,nyeri,fluktuasi,tanda klinik lain yang
jelas seperti demam,keringat malam,berat badan
menurun
 Tampak limfadenopati di hilus atau mediastinum
 Jika bukan PGL anjuran FNAB
 TB MILIER

 Penyebaran TB hematogenik
 Sebagai akibat infeksi primer atau erosi
lesi TB ke pembuluh darah
 Sering menjadi penyebab wasting yang
tidak ter diagnosis pada stadium terminal
 Anamnesis keluhan batuk, nafsu makan
berkurang sesak nafas, demam dan gejala
lain yang berhubungan dengan organ
terkait
 Keadaaan umum buruk,suhu meningkat dan
sesak nafas
 Pembesaran hati,limpa,kaku kuduk dan
koroid tuberkel
 Pada funduskopi koroid tuberkel merupakan
patognomonik TB millier
 CXR gambaran bercak bercak milier tersebar
pada ke 2 lapangan paru
 Pemeriksaan Lab BTA pada cairan tubuh
 Biopsi mencari per kijuan
 Diagnosis banding dengan : slim disease,
bakterimia, karsinoma diseminata, infeksi
diseminata mikobakteria atipik dan
tripanosomiasis
 EFUSI PLEURA TB
 Anamnesis ditemukan keluhan sesak nafas,nyeri
dada dan demam tinggi
 Pemeriksaan fisik : perkusi suara pekak,suara nafas
melemah,pergerakan dada ada sisi yang tertinggal
 Pemeriksaan penunjang : Foto toraks P/A dan
lateral
 Pungsi aspirasi jangan >1500 cc, lihat makroskopis
dan periksa rivalta dan analisis cairan pleura ( sel,
monosit, limfosit, glukosa,protein) dan BTA
langsung, kultur, resistensi
 Prevalensi TB yang tinggi menyebabkan kasus efusi
pleura dianggap sebagai TB
 MENINGITIS TB
 Anamnesis mulai dari sakit kepala sampai
kesadaran menurun dan tidak bisa menundukkan
kepala
 Kaku kuduk dan Kernig sign
 Obstruksi sisterna basalis akan terjadi hidrosefalus
 Pungsi lumbal tampak jernih santokrom, tekanan
dan jumlah lekosit > 5000 sel/mm³ terutama
limfosit,protein » dan glukosa menurun
 Pungsi lumbal berbahaya jika pasien mengalami
gangguan fokus neurologik atau funduskopi tampak
edema papil
 OAT lebih aman dari pada pungsi lumbal
EFUSI PERIKARDIUM TB
 Keluhan lemah dan pusing, nyeri dada, nafas
pendek, batuk, nyeri hipokondrium kanan dan kaki
bengkak
 Pemeriksaan fisik : takikardia, TD rendah, pulsus
paradoksus, JVP », suara jantung tak terdengar,
friction rub
 Tanda gagal jantung kanan (asites,edema tungkai )
 Radiologik kardiomegali, lapangan paru bersih,
terdapat cairan pleura
 EKG, Ekokardiografi
 Perikardiosentesis
 Treatment
 adherence is very important*  Total 9 months of anti
 6Mo vs 9Mo (Similar response rates 98.5% TB for
vs 94.5%*)
 delay clinical,
 Induction - 2 months microbiological
– Isoniazid [INH]
Rifampicin [RIF] response (positive
Pyrazinamide [PYZ] C/S at 2 mo.)
Ethambutol [EMB]
 cavitary lesion
 Consolidation - 4 months
– Isoniazid + Rifampicin for 4 months  No PZA during first 2
months
 Consolidation – 10 months
– Isoniazid + Rifampicin for 10 months
in TB meningitis or tuberculoma
 Every effort should be made to use a Appropriate timing
rifamycin-based regimen for the entire of initiation of HAART
course of therapy

ATS, CDC, IDSA: MMWR June 20,2003

50
*Swaminathan S 12th CROI; February 22-25, 2005;. Abstract 141
Kategori Klasifikasi Fase insentif Fase lanjutan
dan jenis

I Kasus Baru BTA (+) 2HRZE * 4 H3R3*

Kasus Baru BTA (-) 2 HRZE 4 HR
Ro (+) lesi luas
Kasus Baru EPTB 2 RHZE 6 HE
berat

II Kambuh ( relaps) 2 HRZES/ 1 HRZE * 5 H3R3E3 *

Gagal/failure 2 HRZES/ 1 HRZE 5 HRE
Putus Obat/after
default

III Kasus baru BTA (-) 2 HRZ * 4 H3R3 *

Ro (+) sakit ringan 2 HRZ 6 HE
Kasus EPTB ringan 2 HRZ 4 HR

IV Kasus Kronik Obat second line

 Differential Diagnoses of
Pulmonary TB
Bacterial Pneumonia
PCP
Fungal pneumonia
Non-infectious causes- KS

PCP Pen.m Nocardia Crypto. n KS 55

Challenges in Treatment
TB AND HIV

Two Diseases
One Patient
56
 ARV in TB/HIV coinfection

TB and HAART - problems

 Pill burden/adherence
 Overlapping toxicity profiles
 nausea, vomiting, rash,
hepatitis, neuropathy
 Drug-drug interactions
 Rifampicin a strong enzyme
inducer
 ‘Paradoxical worsening’ of
TB
 immune reconstitution
reaction
 more likely if HAART started 57

early in TB treatment
What are the Benefits of
Antiretroviral Therapy
(ART) on
TB and mortality

58
 Comparison of survival rate among
TB/HIV patients with/without ART
Retrospective study : 01/2000-12/2004
1087 patients, mean CD4 =49(19-129) cells/mm3
p<0.001
99 99 97
ARV
100 89
77 without ARV
80
survival rate

64
60 The mortarity
40
rate was reduced
for 80%
20
0
1 year 2 year 5 year 59

Manosuthi W et al J AIDS 2006; 43:42-6

 How to Treat HIV patients
co-infected with
Tuberculosis ?
There some Challenges :
• When to start Antiretroviral Therapy
• What ART regimen to start
• Immune Reconstitution syndrome (IRIS)
60
 When to start HAART in TB-HIV
Patients
2 mo 6 mo
4 wk

2 wk

Anti-TB

? Await for Randomized controlled trial results

61
 Randomized
“When to Start ART
Treatment in TB” Studies
Trial CD4 ART ART
Sponsor Number Randomization
CAMELIA <200 EFV/D4T/3TC ART 2 vs 8
ANRS1295/NIH N=660 weeks
AA5221 <200 EFV/TDF/FTC ART 2 vs 8-12
NIH N=800 weeks
START >50 DDI/3TC/EFV During vs after
NIH N=592 TB treatment

Blanc, 2006 62
 Potential Benefits and Risks of
Starting ART Immediately With TB
Treatment
BENEFITS RISKS
•
•
Reduced morbidity
Reduced mortality
Increased toxicity to
• Improved TB outcome TB and ART therapy
Drug interactions
between HIV and TB
medications
Pill burden
Immune
Reconstitution
Syndromes (IRS)
63
Dean, AIDS, 2002; Pedral-Sampaio,2004, Brazil JID;
Harries, Lancet, 2006; Lawn, Lancet ID, 2005 Modified from D. Havlir
Don’t Wait till it’s too late !

 Mortality rate 16-35% in TB-HIV

without ARV (4-9% in HIV negative)
 The lower CD4 is the higher mortality
rate
 Mortality rate fell by 72% after
introduction of HAART
Ya DM et al AIDS 2001;15:143-52; Greenberg AE et al. AIDS1995;9:1251-54
Ackah AN et al Lancet 1995;345:607-10; Kang’ombe CT et al Int J Tuberc Lung Dis
829-36; Dean GL et al AIDS 2002;16:75-83 64
 Treatment of HIV and
TB
Practical Approach
Start 4-drug Currently On HAART ?
TB regimen

No
Yes

CD4 <200 CD4 200-350 CD4 > 350

Continue
and adjust ARV
Begin Begin and dosages
No
HAART HAART HAART
in 2-8 wks in 2-6 mos 65
What ART regimen to
start ?

66
 67

D. Havlir 2006
 Drug-drug interactions
TB/HIV
Absorption Rifampicin

Metabolism ↑CYP3A4
Antiretrovirals
• PIs
•  NNRTIs
Metabolism

Elimination
Effect of Rifamycins on ARV drug
levels
Anti-TB SQV IDV NFV APV LPV NVP EFV

Rifampin -84% -89% -82% -82% -75% -37% -25%

Rifabutin -40% -32% -32% -15% 0 -16% 0

Finch et al. Arch Intern Med 2002;162:985-9269

 NNRTIs and RIF
Do we need to adjust the NNRTI
doses ?
Small PK studies support dose
increase
– EFV to 800 mg qd
– NVP to 300 mg bid
However, clinical outcome studies to
date do not support dose adjustment
of EFV or NVP
70
What should we recommend for Asia ?
When combined NNRTI+ RIF
For Asian Populations or Patients
with low body weight
• EFV can be dosed at 600 mg qd
• NVP 200 mg BID is efficacious
and should avoid the first 2 weeks
lead-in (because 80% patients had
suboptimal NVP levels)
71
 Overlapping toxicities of
Anti-HIV with Anti-TB

72

D. Havlir 2006
TB ART TREATMENT PLAN
High risk behavior for HIV
TB infected

Group 1:
HIV + and no TB
Group 5:
HIV - and
active TB

Group 4:
HIV - but high risk
behavior and active
Group 2: TB
HIV + with latent
TB infection

Group 3:
HIV + and active TB
 HIV at risk TB infected

Group 1:
HIV (+) but TB uninfected
•BCG (for small children,
asymptomatic HIV)
•Continuous HIV/AIDS care
•HE for HIV (and TB),
including screening for
STIs, condom promotion
and safe IDU
•Continuous monitoring for
Active TB
 HIV at risk TB infected

Group 2:
HIV (+) with TB infected
•PT for TB infected
•Continuous HIV/AIDS care
•HE for HIV (and TB), including
screening for STIs, condom
promotion and safe IDU
•Continuous monitoring for
Active TB
HIV at risk TB infected

Group 3:
HIV (+) with Active TB

•DOTS
•Continuous HIV/AIDS care
•HE for HIV and TB, including
screening for STIs, condom promotion
and safe IDU
•Cotrimoxazole during TB treatment
HIV at risk TB infected

Group 4:
HIV (-) but at risk
with Active TB
•DOTS
•HE for HIV and TB,
including screening
for STIs, condom
promotion and safe
IDU
HIV at risk TB infected

Group 5:
HIV (-) with
Active TB
•DOTS
 HIV at risk TB infected

Group 1:
HIV (+) but TB uninfected
•BCG (for small children, Group 5:
asymptomatic HIV)
HIV (-) with
•Continuous HIV/AIDS care Active TB
•HE for HIV (and TB), •DOTS
including screening for
STIs, condom promotion
and safe IDU Group 4:

•Continuous monitoring for HIV (-) but at risk

Active TB
Group 2:
HIV (+) with TB infected
•PT for TB infected
•Continuous HIV/AIDS care
•HE for HIV (and TB), including
screening for STIs, condom
promotion and safe IDU
•Continuous monitoring for
Active TB
with Active TB
•DOTS
Group 3:
HIV (+) with Active TB •HE for HIV and TB,
including screening
•DOTS for STIs, condom
•Continuous HIV/AIDS care promotion and safe
IDU
•HE for HIV and TB, including
screening for STIs, condom promotion
and safe IDU
•Cotrimoxazole during TB treatment
FAITH, HOPE, AND
........LOVE