Koinfeksi TB-HIVdan PermasalahannyaAdrianison

Dept Pulmonologi dan Ilmu Kedokteran Respirasi FKUR/RSUD AA

PENDAHULUANTB masalah kesehatan utama di IndonesiaMenyerang dewasa muda : 80%Penyebab utama meningkatnya TB HIV/ AIDSSKRT Dep.Kes 2001 : TB rangking 3TB penyebab kematian utama dari penyakit infeksiTB merupakan komplikasi serius pada 50-70% kasus AIDS di AsiaPenyebaran HIV/AIDS di Asia paling cepat di dunia

TB - HIV Interaksi dan KoinfeksiPeneybab kematian utama penderita HIV di duniaHIV : infeksi TB sakit TBPenderita HIV : risiko kena TB selama hidupnya 50% dibanding non HIV 5-10%HIV + infeksi lain spt TB progresifitas HIV meningkatTB pada HIV bisa memberikan gambaran klinis dan radiologis yang tipik atau atipik. Atipik immunosupresi yang berat

Imunosupresi ringan:Gambaran foto toraks khas (tipik):Infiltrat di lobus atas dan atau bilateralkavitasfibrsosis

Gambaran klinis sering menyerupai TB post primerBTA sputum biasanya positif

Arrow points to cavity in patient's right upper lobe--typical finding in patient with TB

Imunosupresi berat :

gambaran klinis tidak khas (atipik), menyerupai tb primer:BTA sputum sering negatifFoto toraks infiltrat interstitial terutama di lobus bawah, tapa kavitas dab fibrosisGambaran foto torak sering disangka pneumonia

X-ray in a TB patient may look like this one of a patient with confirmed PCP.

HIV yang lanjut TB disseminata dan ekstra paru karena immunitas yng rendah tak mampu menghambat pertumbuhan dan penyebaran lokal kuman TB. Infiltrat di lobus bawah, unilateral atau bilateral lebih sering dari di lobus atas dan kavitas.Bentuk TB paling umum adalah limpadenitis, pleural effusi, perikarditis, TB milier, meningitis

Source HIV Subdir.-CDC

> 5 % PAPUA, DKI, West JAVA, East JAVA, BALI, RIAU, West KALIMANTAN

3 5 % Central SULAWESI, LAMPUNG, North SUMATERA,South SULAWESI, DIY

1 3 % Central JAVA, BENGKULU, East NUSA TENGGARA, East KALIMANTAN, North SULAWESI, BANGKA BELITUNG

< 1 % Other PROVINCES

Situation of HIV prevalence in high-risk groups (sentinel surveillance)

Estimasi Distribusi ODHA 10 Provinsi Tertinggi di Indonesia 2009

FaktaPaling sedikit 1 dari 3 Odha

akan terkena TB

Kumulatif Infeksi Oportunistik yang dilaporkan di IndonesiaSumber: Subdit AIDS & PMS, Depkes RI, s/d 31 Des 2008

No.Jenis Infeksi OportunistikJumlah1.Tuberkulosis8.9862.Diare4.5423.Kandidiasis4.4794.Dermatitis1.1465.Limfadenopati Generalisata Persisten6036.PCP4747.Ensefalopati3868.Herpes Zoster2999.Herpes Simpleks14110.Toksoplasmosis10411.Lain-lain197

Dampak TB terhadap HIVTB mempercepat progresi HIV TB merupakan penyebab kesakitan dan kematian utama pada OdhaTB mempengaruhi ART dengan macam2 cara

Efek TB terhadap HIVTB menginduksi replikasi HIV dalam limfosit pada orang terinfeksi HIVSecara in-vitro, TB mengaktifkan ekspresi laten HIV pada sel monocytoidViral load lebih tinggiKetahanan hidup lebih singkat

Efek HIV terhadapTBMeningkatkan insidensi dan prevalensiMengubah manifestasi klinisMenyulitkan diagnosisMembuat terapi lebih menantangMeningkatkan morbiditi dan mortaliti

Pasien HIV: Perkembangan TBRisiko infeksi/reaktivasi TB meningkat sejalan dgn turunnya jumlah CD4 (tetapi dpt terjadi pd berapapun jumlah CD4)Berhubungan dgn gangguan respons Th 1 (cell-mediated immunity)Berhubungan dengan penurunan delayed type hypersensitivity terhadap tes tuberkulin dgn menurunnya CD4

Berhubungan dgn supresi respons proliferatif in-vitro terhadap antien TBSistem imun tdk dapat melawan basil; biasanya tdk terdpt Ghon complexMeningkatkan risiko TB diseminataPasien HIV: Perkembangan TB

Dugaan Infeksi HIV pada pasien TB

Kapankah pemeriksaan uji HIV pada pasien TB ?

Dimana:Didaerahdg prevalensi HIV tinggi Siapa:PasienTB dg risiko tinggi terken infeksi HIV Bgmn:PasienTB dengan keluhan tanda/ gejala yg menimbulkan dugaan HIV

Daerah dengan prevalensi tinggi: Sub-Sahara Afrika Indonesia ; beberapa daerah tertentu di:

Papua, Jakarta, Jawa Timur dan Jawa Barat, Bali, Kepri, Kalimantan Barat, Jawa Tengah dan Sumatra Utara

Kelompok orang dengan risiko tinggi:

Pengguna narkoba suntikPekerja seks komersialBiseksualHomoseksualNarapidana

TB and HIV

Gambaran klinis TB pada Ps suspek HIV Gejala klinis TB ditambah kelainan dibawah ini :

Penurunan berat badan >10kg (atau >20% dari berat badan) dalam 4 bulan Diare >1 bulan Nyeri saat menelan (odynophagia) Perasaan terbakar di kaki (neuropathy)

Tanda :Bekas herpes zosterSkin rash yg gatalLesi kulit atau membran mukosa yg berwarna gelap atau kemerahan (Kaposis sarcoma)Limfadenopati generalisataOral CandidiasisOral hairy leukoplakiaNecrotizing gingivitisAphthous ulcers (severe or recurrent)Persistent painful genital ulcerationAngular chelitis

Angular Cheilitis

Gejala Klinis TB pada Penderita HIVtidak sama dengan gejala umum TB

Demam dan penurunan berat badan merupakan gejala yang pentingBatuk bukan gejala yang umumBanyak variasi pada gambaran foto toraksLebih banyak TB ekstra paru dan TB disseminataDiagnosis diferensial lebih luas

Lokasi TB Ekstraparu yg sering ditemukan

Lymph Nodes: Cervical > axillary> inguinalSerosal disease: pleural, pericardialGenitourinary tractCentral nervous system: meningitis, tuberculomaBone and jointSoft tissue abscessesDisseminated disease

Pengobatan TB -HIVPada dasarnya pengobatannya sama dengan TB tanpa HIV/AIDS strategi DOTS WHO : paduan obat dan lama pengobatan sama yaitu sesuai kategoriDiantara infeksi oportunistik pada pasien ODHA infeksi TB paling reponsifPada meningitis, TB milier, spondilitis, kelainan neurologik fase lanjutan diperpanjang 6- 7 bulan ( total 8-9 bulan) Thiocetazon (tak ada di Indonesia) jangan diberikan karena sangat toksikStreptomisin harus dijamin sterilisasinya

Koloborasi TB/HIVKoordinasi program TB - HIV diperlukan utk :

Mencegah HIV pada pasien TBMencegah TB pada pasien HIVPemeriksaan pasien dan kontak (untukTB dan HIV)Koordinasi pengobatan dan penyediaan obat

Pemberian OAT dan ARVPemberian OAT dan ARV perlu memtimbangkan:Interaksi antar obat-obat yang digunakanPeran antiretroviral therapy (ART)Overlap efek samping obatImmune-reconstitution inflammatory syndrome (IRIS)Masalah kepatuhan pengobatan

Pemberian ARV pada Pasien TB-HIVIndikasipemberianART padapasienTB/HIVberdasarkan:Status penyakit HIV (kadar CD4)Keberhasilan pengobatan dan paduan OAT yang sedang dilakukanKepatuhan pengobatan dan efek sampingJika belum diobati dengan ART pada saat diagnosis TB, keputusan untuk memulai ART didasarkan faktor2 berikut.

Pedoman WHO, 2006

Memulai lini pertama ART yg berkaitan dgn mulainya terapi anti-TBJumlah CD4Anjuran ARTWaktu ART berkaitan dgn mulainya terapi anti-TBCD4 200 sel/mm3ART dianjurkan aAntara 2-8 minggu bCD4 antara 200-350 sel/mm3ART dianjurkanSetelah 8 minggu CD4 350 sel/ mm3Jangan memulai ART cRe-evaluasi pd 8 minggu dan pd akhir terapi TB

Memulai Antiretroviral pada pasien TB HIV dalam OAT jika CD4 tak bisa diperiksa

GAMBARAN KLINIK

Adanya TB paru dan tanda HIV advanced , atau tidak ada perbaikan secara klinis; adanya TB ekstra paru

TB paru BTA negatif, berat badan bertambah dengan pengobatan, tanpa tanda/gejala HIV advanced

TB paru BTA positif, berat badan bertambah dgn pengobatan, tanpa tanda/gejala HIV advanced

ARV

Mulai ART begitu pengobatan TB tidak disertai efek samping ( 2 8 minggu OAT)

Mulai ART setelah OAT fase intensif selesai

Tunda ART sampai pengobatan TB selesai

Pasien TB Diduga Menderita HIV/AIDSAda riwayat perilaku risiko tinggi tertular HIV/AIDS Penderita TB yg cepat memburuk KU nyaHasil pengobatan OAT tak memuaskanMDR - TB TB Kronis

Clinical Features Suggestive of HIV co-infection in TB patients

AFB SMEAR POSITIVE IN PATIENTS PULMONARY TB WITHOUT HIV IN INDONESIA

AFB SMEAR NEGATIVE IN PATIENT PULMONARY TB WITH HIV (+) IN INDONESIA

Obat ARV di Indonesia

Nama Generic GrupNama MerekZidovudine/AZTNRTIZidovex, AntivirLamivudine/3TCNRTIHiviralStavudine /d4TNRTIStavir, ZeritDidanosine /ddlNRTIVidex

NevirapineNNRTINeviralNelfinavirPINelvex

Efavirenz/EFZNNRTIEvafir

Zidovudine + LamivudineDuviralStavudine + LamivudineCoviro-LS3*Stavudine + Lamivudine + NevirapineTriomune, GPOVir

Pedoman WHO (2006): Rejimen ART Lini Pertama & TB aktif1 ZDV/3TC/ABC atau ZDV/3TC/TDF2 Reaksi hipersensitivitas*Penyuluhan pasien, kunjungan 2x/minggu, ALT/AST pd 0,2,4,8 dan 12 minggu

RejimenRekomendasiMonitoringEFV/2NRTIDisukaiKehamilanNVP/2NRTIPilihanALT*Triple NRTI1PilihanHSR2 dgn abacavir

Immune Reconstitution Inflammatory Syndrome (IRIS)

Definisi IRISPenyakit laten atau masih dlm masa inkubasi berkembang menjadi simptomatik atau bahkan memburuk setelah pemberian ARTReaksi paradoksal ; memburuknya gejala IO yg sudah mendapat pengobatan, segera setelah pemberian ART

TB-IRIS

Reaksi TB-IRISInsidens: 8-45%Median: 2-4 minggu setelah memulai ARTFaktor RisikoInterval yg pendek antara terapi TB dan memulai ARTTB disseminata (menyebar)Jumlah basis CD4 rendah dan jumlah basis VL tinggiCD4 yang cepat meningkat akibat ARTVL yang cepat turun akibat ARTKomplikasi ini dpt mengancam hidup tetapi angka kematian jarang Lawn 2005, Shelburne 2005, Breton 2004, Narita 1998, Michailidis 2005,Ollala 2002, Breen 2004, Kumarasamy 2004, Lawn 2007

Definisi kasus Kriteria KlinisMajor 1)Pembesaran KGB atau KGB yg baru, abses dingin atau timbulnya infeksi fokal2)Gambaran radiologi (TB) memburuk/baru timbul3)Timbulnya meningitis TB atau lesi fokal di SSP yg baru/membesar4)Serositis yang baru atau memburuk

Minor 1)Gejala konstitusional mis, demam, keringat pd malam hari >>2)Gejala respirasi - mis, batuk, sesak napas, stridor3)Nyeri perut dan/atau pembesaran hati

1 major atau 2 minor

Pengobatan kortikosteroid Beberapa laporan kasus menunjukkan respons Timbul beberapa komplikasi yg poten SK, reaktifasi herpes & efek samping lainBanyak kasus sembuh sendiriDosis dan lamanya?

Fishman JE et al. AJR 2000; 174:43-49

*Concentrated level epidemic (DKI Jakarta, Papua, Bali, Riau, West Java, East Java)

However in other provinces namely West Kalimantan, N.Sumatra, N.Sulawesi significant increase in the last 4 years

Up to December 2004, out of a total of 2,682 AIDS cases, 44% were reported IDUs, and 3,368 HIV infection reported from 30 provinces.

Main mode remains sexual transmission, but new infections among IDU is increasing alarmingly.

HIV prevalence in IDUs has reached to 50 % in most big provinces such as Jakarta, Bali, West Kalimantan, and West Java.

*****For reasons that will be discussed, TB hastens the rate of HIV progression. In TB infection CD4 cells are essential for optimal macrophage bacteriocidal activity to destroy the TB bacillus. These CD4 cells become activated. This dual threat hastens the rate of HIV disease progression.This ancient and common disease is the leading cause of illness and death among PLWH in developed as well as in developing countries. With waning immunity caused by HIV infection there is an enormous increase in tuberculosis case rates. In one Haitian study where tuberalin conversion in childhood is almost universal the rate of active tuberculosis in AIDS patients is 60%.ARV is influenced by the co-existence of TB. When a person with TB is diagnosed with HIV disease there is often a question about when to start ARV.When a person with HIV is diagnosed with TB the worry is how can we treat HIV and TB at the same time.When you diagnose them together the question is which to start first.

*TNF = Tumor Necrosis FactorThere is some evidence to suggest that TB has an impact on the replication of HIV within lymphocytes.Studies have shown that TB impacts HIV plasma levels and can cause increase of HIV RNA viral load.*In looking at global maps one can transpose high seroprevalence rates of HIV disease upon global maps showing a high incidence of tuberculosis infections. This would maybe be a helpful visual rather than just words.The clinical disease presentation of TB in the HIV infected patient may be similar. However, there may be more atypical presentations with more extra-pulmonary TB including TB bacteremia, fistula formation and CNS involvement.The diagnosis can be evasive since many of the features of TB are common in HIV as well (fever, wasting, lymphadenopathy). Likewise in remote areas it may be difficult to do the appropriate laboratory and radiologic studies needed to make the TB diagnosis.Treatment in HIV disease can present a challenge. If there is no drug resistance patients and patients can tolerate treatment they do well. These patients must be induced on a four drug regimen. When placed on ARV the HIV positive patient must be monitored carefully due to numerous and complex drug interactions.Morbidity and mortality in the HIV infected is increased. Co-infected patients have a 5 to14 fold increase risk of dying (from co-infection with other OI as well as the TB) with MDR (multiple drug resistant TB) prognosis is even worse.There is an additional strain on infrastructure hospital beds are filled.

*Because of the essential role of the CD4 cell in the control of TB, the risk of reactivation and acquisition of TB increases with the decrease of CD4 cells. Keep in mind, however, that infection with and reactivation of TB can occur at any CD4 count. In murine modes, the TH 1 subclass (T helper cell 1 subclass) which secrete gamma interferon and interleukin 2 are necessary for the control of Tb. This is more complex in humans but nevertheless may account for incomplete killing of the TB bacillus within the granuloma. With already defective T cell responses, the HIV-infected person will not be able to respond in the usual fashion to TB infection.During the course of HIV disease the incidence of positive TST is reduced. A 5 mm induration in HIV-infected persons is considered positive, and some experts would say that 2 mm induration is positive. To complicate matters, many patients with advanced AIDS and low CD4 counts are anergic and will have a negative TST despite exposure to or the existence of active TB.

*In advanced HIV disease, the responses to TB antigens are unable to respond in the usual way. The clinical and immunologic picture of TB during HIV disease is determined by the degree of immunocompromise.Granuloma formation is enhanced by TNF and chemokines are important of cellular recruitments to this granuloma. The granuloma formed in immune competent hosts is well circumscribed and the cytokines such as interleukin 10 (IL 10) are used to control the inflammatory response. In HIV infection especially in advanced disease granuloma and cavitation are not present. The immune system is rendered incapable of walling off or isolating the bacillus or in destroying it.As a result of the above phenomena the risk of disseminated TB is increased and is usual in advanced HIV disease**Of course, the notion is that in an HIV+ pt with active TB, TB treatment is given priority.

However, the more severe the HIV status (here expressed by the CD4 cell count threshold), on the left column, the earlier is the initiation of ART in patients with active TB, right column.

These recommendations are informed by the best current evidence available, programmatic experience and expert opinions.

In situation with no availability of CD4 cell count, there is the notion of over-treatment.

For specific TB diagnosis such as Lymph Nodal TB, ART could be either delayed or deferred but this is specified in the document that is available on line.

*Concerns of EFV-induced fetal effects stem from animal studies, the predictive value of animal data for humans is unknown. . In a prospective pregnancy registry, in a recently published article in AIDS research and Therapy, no increase was detected in overall risk of birth defects following exposure to EFV in the first trimester-

AIDS research and Therapy 2006, 3:11

**There are two forms of TB-IRIS:The first being the unmasking of active TB by ART, TB that was unrecognised at the start of ART because the patient was either asymptomatic or minimally symptomatic but presents soon after ART initiation unmasked by the recovering immune system.The second being paradoxical deterioration in patients diagnosed with TB and on TB treatment prior to starting ART. These paradoxical reactions may manifest with enlargement of lymph nodes, cold abscesses or effusions, worsening of pulmonary infiltrates or with life threatening neurological involvement as well as other manifestations soon after ART initiation.

*This slide briefly summarises what we do know about this condition from a number of retrospective studies. Among cohorts of patients started on ART while on TB treatment the incidence is reported between 8-45% with the onset usually 2-4 weeks after ART is initiated. Risk factors variably identified are shorter delay between commencing TB treatment and ART, disseminated TB, baseline CD4 and VL and response of these to ART. Among cases reported in the literature mortality is rare but life threatening complications such as splenic rupture and respiratory failure are described. *Furthermore patients should fulfil one major or two minor clinical criteria for the diagnosis. The major criteria were defined as

*Regarding the treatment of TB-IRIS: Steroids and non-steroidal anti-inflammatories have been used with anecdotal reports of response. However there are potential hazards with steroids such as the development of Kaposis sarcoma, reactivations of herpes virus infections and other steroid side effects. The fact that many cases of TB-IRIS are self limiting also needs to be considered. Thus the role of steroids in TB-IRIS has not been clearly defined and issues regarding dose, duration, route of administration and potential drug interactions also need to be addressed in studies. **TB epidemic has been well controlled by great efforts of TB DOTS Program.But HIV is now fuelling TB epidemic.