TB RO pada Kondisi Khusus

(HIV dan Ekstra Paru)

Nastiti Kaswandani

Departemen Ilmu Kesehatan Anak FKUI/RSCM

Ikatan Dokter Anak Indonesia

TB Resisten Obat pada Anak HIV

 150
operational

Rate pe

Nu
100
target
Notified (new and relapse)

TUBERCULO
50

GLOBAL
0

vdd
2000 2005 2010 2015 2019

REPORT
DRUG-RESISTANT TB TB/HIV
6000 MDR TB
TB MORTALITY 2000-2019 beredar di sekitar
(EXCLUDES PEOPLE WITH HIV)
anak-anak
• tdfmdkvt
Estimate24
Treatment success rate
000 160 000

140 000
11 463
laboratory confirmed 19 000
people fell ill
120 000
5 531 people living with HIV

Number of deaths
100 000
started on
with
% drug-resistant TB
83 80 000

60 000

40 000
second-line treatment
2020 End TB milestone
fell ill with TB
20 000

TB PREVENTIVE TREATMENT -
2000 2005 2010
TB CATASTROPHIC
2015 2019
COSTS
TB/HIV

19 000
%
017 %
11 708
notified
7000
lebih tidak
ternoti kasi
12 9.4
HIV-positive people
Data not available
(aged > 5 years) household
Data not available
people living (aged
with
(newly enrolled HIVhousehold contacts
<5 years)
4 995
contacts of bacteriologically
of bacteriologically confirmed TB
in care) on TB notified
confirmed TB casesand on TB patients facing
nt fell illcaseswith
preventive treatment TB treatment
on TB preventive antiretroviral
on TB preventive treatment* treatment catastrophic total costs

TB-SDG MONITORING FRAMEWORK

CATASTROPHIC COSTS TB FINANCING 2020
fi
 Anak dengan TB-RO/HIV
• Pasien anak HIV positif merupakan kelompok yang rentan TB,
termasuk TB RO
• Angka kematian meningkat terutama jika komorbidnya
(HIVnya) tidak berada dalam kondisi yang stabil
• Semua anak yang terdeteksi TB RO harus dilakukan
pemeriksaan HIV
• Prinsip dan paduan pengobatan TB RO pada HIV sama
dengan pasien bukan HIV
• Kompleksitas permasalahan dan manajemen TB-RO/HIV
memerlukan kerjasama tim TAK, bila mungkin dengan ahli
imunologi/infeksi

Risiko TB RO pada Anak HIV

DST known HIV-infected HIV-uninfected OR (95% CI) &
corrected P-value

All with DST/HIV 357 (20.5%) 1381 (79.5%)

(n=1738)
Susceptible 290 (81.2%) 1179 (85.4%)

All resistance 67 (18.8%) 202 (14.6%) 1.35 (0.99-1.83); p=0.065

INH mono- 18 (5.0%) 82 (5.9%) 0.84 (0.49-1.43); p=0.603

resistant
RIF mono- 11 (3.1%) 20 (1.4%) 2.16 (1.03-4.56); p=0.064
resistant
MDR 38 (10.6%) 100 (7.2%) 1.52 (1.03-2.26); p=0.044

All RIF resistance 49 (13.7%) 120 (8.7%) 1.67 (1.17-2.38); p=0.006

 Tantangan dalam Permasalahan TB RO
pada Anak HIV
• Penegakan diagnosis TB
• Penegakan MDR terkait spesimen bakteriologis dan
pemeriksaan bakteriologis
• Pemberian obat TB RO dan pilihan ARV
• Pilihan paduan dan interaksi obat
• Banyaknya jumlah obat dan keteraturan
pengobatan
• IRIS
• Efek samping dan toksisitas obat

 Diagnosis TB RO pada HIV

• Konfirmasi TB RO secara bakteriologis:
• Pengumpulan spesimen yang memadai
• Akses TCM dan biakan TB
• DST pada pasien TB yang biakannya positif
• Presumptive TB RO:
• Sumber infeksi TB RO atau gagal terapi
• Perburukan gejala pada lini pertama

Management of Drug-
Resistant Tuberculosis
in Children: A Field
Guide. The Sentinel
Project for Pediatric
Drug-Resistant
Tuberculosis; Febr
2019, 4th ed.
 Inisiasi pengobatan TB RO dan ARV

• Pasien TB RO dengan HIV yang sudah memulai pengobatan

antiretrovirus (ARV), maka ARV diteruskan dan obat TB RO
dapat segera diberikan sesudah diagnosis ditegakkan.
• Pada anak HIV yang belum mendapatkan ARV, pengobatan ARV
harus dimulai dalam 2 minggu setelah inisiasi pengobatan TB
RO, kecuali pada kasus TB RO meningitis yang dimulai dalam
waktu 4-6 minggu untuk mengurangi risiko IRIS intrakranial
• Ketika memulai pengobatan ARV dan TB RO, perlu diperhatikan
efek samping yang tumpang tindih akibat ARV dan OAT lini
kedua, serta jumlah pil yang diminum
• Regimen ARV harus dipilih untuk menghindari potensi toksisitas
dengan OAT lini kedua.

 MASALAH INTERAKSI OBAT HIV dengan TB RO

• Bedaquiline: Bdq tidak dapat diberikan bersama EFV,

karena akan menurunkan konsentrasi Bdq. Bdq dapat diganti
dengan delamanid atau Bdq tetap diberikan namun EFV diganti
dengan nevirapin/NVP atau lopinavir/ritonavir.

• Linezolid: Lzd dapat menyebabkan supresi sumsum tulang,

pemberian bersama dengan zidovudine (AZT) akan memperberat
efek supresi sumsum tulang. AZT dapat dipertimbangkan diganti
dengan tenofovir (TDF) atau abacavir (ABC) bila terdapat gangguan
ginjal.

• Sikloserin/terizidon: pemberian sikloserin/terizidon bersama EFV

dapat meningkatkan timbulnya gangguan psikiatri











Standard Pelayanan TB/HIV juga
tercantum dalam PNPK HIV 2019
Tantangan Pengobatan
TB/HIV RO pada Anak

• Pemberian obat ARV dan TB RO, suplemen dan

lainnya berjumlah sangat banyak
• Formula “child-friendly” belum available
• Meningkatnya efek samping/ toksisitas obat
• Keteraturan pengobatan
• Care-giver biasanya juga merupakan pasien TB/
HIV

 2015, 19 (8):969-78 Int. J. Tuberc. Lung Dis.

• 4812 abstracts and articles, 30 studies : 2578 adults and 147 children.
• Overall pooled treatment success was 83.4% (95%CI 74.7–92) among children. Mortality was
11.4% (95%CI 5.8– 17.1) in children.
• Loss to follow-up was higher among adults (16.1%, 95%CI 9–23.2) than among children
(3.9%, 95%CI 0.9–6.9)
• Adverse events were experienced by the majority of patients; however, this was inconsistently
documented. The use of uoroquinolones, aminoglycosides and Group IV drugs appeared to be
associated with treatment success.

CONCLUSION: The proportion of HIV–MDR-TB-co- infected patients achieving treatment

success was similar to success rates reported among MDR-TB patients in general, regardless of
HIV status; however, mortality was higher, particularly among adults, highlighting the need for
early diagnosis and more effective treatment regimens.

fl

• The most common outcome was cure (34.9% cured in the pooled analysis), followed by death
(18.1% in pooled analysis). ART uptake was high, at 83% in the pooled analysis. Cure ranged
from 28.6 to 54.7% among patients on ART and from 22.2 to 57.7% among those not on ART
medication. MDR-TB and HIV co- infected patients were less likely to be successfully treated
than HIV negative MDR-TB patients (Risk Ratio = 0.87, 95% CI 0.97, 0.96).
Conclusion: Treatment outcomes for MDR-TB and HIV co-infected patients do not vary widely
from those reported globally. However, treatment success was lower among HIV positive MDR-
TB patients compared to HIV negative MDR-TB patients. Prompt antiretroviral initiation and
interventions to improve treatment adherence are necessary.
 Expert Opinion Drug Safety 2016 – Schaaf et al

Alphabetical Toxicity list – which drug causes what?

• Arthralgia/arthritis: FQNs/PZA/RFB
• Blood dyscrasias: INH/RIF/PZA/LZD/FQNs/PAS and more
• Central nervous system toxicity: headache, drowsiness,
seizures, weakness, insomnia, hallucinations: FQNs
• Depression/Psychosis: INH/ETO/TZD
• Endocrine effects – hypothyroidism: PAS/ETO,
gynaecomastia: ETO/INH
• Flu-like syndrome: RIF/RFB/PAS
• GIT disturbances – nausea, vomiting, abdominal
pain, diarrhoea: Many! ETO/PAS/FQNs/CFZ/LZD/BDQ

Alphabetical Toxicity List – which drug does what?

• Hearing impair/ototoxicity: AM/KM/CM

Hair loss (alopecia): INH/ETO
• Idiopathic intracranial pressure: FQNs
• Jaundice/hepatotoxicity: PZA/INH/RIF/ETO/PAS/MFX
• K+ decrease: Electrolyte disturbance : CM/PAS
• Lactic acidosis: LZD
• Myelosuppression: LZD
• Nephrotoxicity: AM/KM/CM/SM
• Optic neuritis/vision disturbance/colour blindness:
EMB/LZD/INH/ETO/PAS

Expert Opinion Drug Safety 2016 – Schaaf et al

 Alphabetical Toxicity list – which drug causes what?

• Peripheral neuropathy: INH/ETO/LZD/TZD

Pancreatitis: LZD
• QTc interval prolongation: FQN/CFZ/
CLA/BDQ/DLM
• Rashes: PZA/FQNs/TZD/PAS and many other
• Skin discolouration – red skin: CFZ
• Tendinitis/tendonopathy: FQNs
• Uveitis: RFB
• Vestibular toxicity: AM/KM/CM/SM
Expert Opinion Drug Safety 2016 – Schaaf et al

TB Ekstra Paru RO
 Insidens TB ekstra paru RO
• Insidens TB ekstra paru pada anak yang terbukti
RO jumlahnya sedikit
• Seringkali menyertai TB Paru
• Kecurigaan RO pada TB EP sama halnya pada TB
paru, mis: sumber penularan RO, atau gagal
terapi, atau tidak respons dengan lini pertama dll
• Jika terdapat kecurigaan TB RO yang memerlukan
konfirmasi spesimen jaringan perlu komunikasi
dengan ahli patologi klinik/mikrobiologi

Padayatchi et al The Pediatric Infectious Disease Journal • Volume 25, Number 2, February 2006

TABLE 1. Summary of Clinical Data in Children With Drug-Resistant Tuberculosis Meningitis

BMRC Time to Time on

Past History History of Steroids
Patient Age (yr) Grading HIV Status Confirmation of Effective Outcome
of TB TB Contact* Used
(on Admission) MDR-TBM (wk) Therapy (wk)

1 3 No Unknown 1 Negative No 16 0 Died

2 2.5 No No 3 Positive Yes 12 0 Died
3 2.5 No Yes 3 Positive No 13 0 Died
4 8 No Yes 1 Positive No 10 48 Survived
5 0.8 No Unknown 3 Negative No 12 0 Died
6 11 Yes Unknown 1 Positive Unknown 10 2 Died
7 4 Yes Yes 2 Positive No 20 8 Died
8 2 No Unknown 2 Positive No 10 8 Died
*The Mycobacterium tuberculosis susceptibility patterns of the TB contacts were not known.
BMRC indicates British Medical Research Council Grading.

OUTCOME
INH, pyrazinamidepasien
(PZA) and Meningitis
Rif, he developedTB neckMDR
stiff- pada
Rif and anak
PZA. Hersangat
aunt, who buruk
was the caregiver, had TB and
ness by week 3. The first lumbar puncture (LP) was normal, was receiving treatment at the time of the child’s diagnosis.
but subsequent LPs were consistent with TBM (Table 1). He Three months after admission, the child developed diarrhea
continued to deteriorate neurologically, and streptomycin and and became irritable. The first Pediatr
LP was only done 1 month
Infect Dis J 2006;25: 147–150)
intravenous Rif were added. He died 4 days later. after this episode and the child died at month seven.
Patient 2. A 2.5-year-old boy presented with fever, loss of Patient 4. A 8-year-old boy presented with loss of appetite,
appetite and weight loss. On admission he appeared ill, weight loss and abdominal pain. His cousin, with whom he
malnourished and pyrexial, he had angular stomatitis, gener- lived, was receiving treatment for TB. The child was pyrexial

 Tata Laksana TB RO
• WHO : paduan TB RO jangka panjang untuk pasien TB RO ekstra paru berat.
• Pengobatan meningitis TB RO paling baik berdasarkan hasil uji kepekaan
OAT dan menggunakan obat-obat yang dapat melewati sawar darah otak.
• Levofloksasin dan moksifloksasin dapat melewati sawar darah otak dengan
baik, begitu juga etionamid/protionamid, sikloserin, linezolid, dan imipenem-
silastatin.
• Isoniazid dosis tinggi dan pirazinamid dapat mencapai kadar terapetik di
cairan serebrospinal, dan mungkin berguna pada kuman TB yang sensitif.
PAS dan etambutol tidak dapat melakukan penetrasi ke susunan saraf pusat
(SSP) dengan baik, dan sebaiknya tidak digunakan pada meningitis TB RO.
• Amikasin dan streptomisin hanya dapat melakukan penetrasi ke SSP bila
terdapat inflamasi meningeal, sementara data mengenai clofazimin,
bedaquiline, dan delamanid dalam penetrasi pada SSP masih terbatas.

 RESUME
• TB RO pada pasien anak dengan HIV dapat meningkatkan
mortalitas, semua pasien TB RO harus dicek HIV
• Tantangan dalam menangani pasien TB-RO/HIV meliputi kesulitan
diagnosis dan kompleksitas pengobatan terkait dengan ARV;
interaksi, efek samping dan keteraturan pengobatan
• TB ekstra paru RO pada anak dapat meningkatkan mortalitas
• Klinisi perlu secara cermat mencurigai RO pada pasien anak
dengan TB EP, serta mengupayakan spesimen yang sesuai untuk
mengkonfirmasi diagnosis TB EP RO
• Paduan TB RO yang dipilih adalah paduan jangka panjang
• Pasien anak TB RO dengan HIV atau EP memerlukan penanganan
TAK multidisiplin, termasuk ahli farmakologi klinik

TERIMA KASIH