Henie Widowati Bagian Penyakit Dalam Fakultas Kedokteran Universitas Trisakti

Latar Belakang

TB masalah kesehatan masy yg besar sejak lama intervensi pcegahan & pengendalian Sepertiga populasi dunia terinfeksi TB Epidemi HIV P meningkat di Asia Tenggara 40% tinfeksi M.Tb ancaman HIV/AIDS (+) & PPD(+) 60% risiko TB aktif HIV/AIDS (-) & PPD (+) 10% risiko TB aktif Sepertiga kasus HIV (+) dunia koinfeksi TB HIV meningkatkan kekambuhan TB meningkatkan risiko penularan

 50% kematian HIV/AIDS oleh px paru dan sal

napas. 23 - 25% kematian pd HIV/AIDS o.k TB risiko kematian 6x lipat terlambat D/ & th/ 5 patogen tsering :
- MTb 37% - PCP 24% - nocardia 6% - criptococcus neoformans 15% - streptococcus pneumonia 6% - strongiloides stercoralis 3%

Respons thd th/ umumnya lambat & dipsulit

oleh ESO dibandingkan status imunologinya

TB incidence closely correlated with HIV prevalence in Africa

1000
Estimated TB incidence (per 100,000 population)

800 600 400 200 0 0 10 20 30 40

WHO

HIV prevalence, adults 15-49y

Two Diseases One Patient

 TB

meningkatkan progresi HIV Infeksi ganda TB-HIV viral loads sangat tinggi Progresi imunosupresi sangat cepat survival memendek walaupun th/ TB telah dilakukan Koinfeksi TB-HIV periode survival menurun dibandingkan HIV tanpa TB

 TB

Penyebab kematian utama pd HIV/AIDS LATE DIAGNOSIS & TERAPI Kesulitan D/ : - sputum sering (-) - >> EPTB - atypical radiografi & presentasi klinis - menyerupai infeksi paru oportunistik yg lain

CD4 counts >350

Disease usually limited to the lungs Often presents like TB in HIV-uninfected persons typical chest X-ray findings with upper lobe infiltrates with or without cavities

CD4 counts <50-100

Extrapulmonary disease is common Disseminated disease with high fevers and rapid progression is seen Chest X-ray findings often look like primary TB with adenopathy, effusions, interstitial or miliary

Features of pulmonary TB

Early Stage HIV infection

Late Stage HIV infection

Clinical picture often resembles

often resembles post-primary PTB primary PTB

Sputum smear often positive result

Chest X-ray appearance

more likely to be negative

upper lobe infiltrates any infiltrates with or lung zone, no without cavitation cavitation; miliary; normal

Skrining 3 kombinasi gejala pada anamnesis : BATUK, DEMAM, KERINGAT MALAM lebih dari 3x seminggu 2. Bila jawaban TIDAK pd 3 gejala tsb kemungkinan TB kecil 3. Bila jawaban YA minimal 1 pada 3 gejala tsb evaluasi d/ lanjutan pemeriksaan sputum BTA & kultur, BJH pd kasus pbesaran kelenjar KGB
1.

Bila sputum BTA (-)....

Kultur BTA sputum the gold standard unt TB diagnosis Bila sputum BTA negative:
Lakukan sputum BTA kultur (bila memungkinkan) Kultur sputum meningkatkan kualitas perawatan & mbantu konfirmasi diagnosis Foto toraks dpt membantu diagnosis, mis. Ditemukan gambaran pbesaran kelenjar di hilus, milier, infiltrat di lobus atas

TB Screening
Tempat/lokasi prioritas unt intensified TB case-finding (ICF):
Medical and infectious disease wards VCT and PMTCT centres Out-patient and emergency room departments Prisons and jails

Impact of ART on TB 0.15 Incidence TB among AIDS patients in Brazil

Annual incidence in AIDS cases
Pulmonary TB

0.10
Disseminated TB

0.05

Mono

Dual

Triple therapy

0.00 1985

1990

1995

2000

www.aids.gov.br/boletim/bol_htm/boletim.htm

Effect of ART on survival

Concomitant HAART markedly improves survival in HIV-infected patients with HIV/TB coinfection. Manosuthi, W et al. JAIDS. 43(1):42-46

Abdool Karim SS, et al. NEJM 2010;362:697-706

Early ART (before 8 wks of TB treatment) Adherence demand Problematic with use of 4-drug for TB and multidrug therapy for HIV

Delayed ART (after 8 wks of TB treatment) Less problematic because fewer drugs necessary for TB treatment Simpler because the number of drugs for TB treatment is less and there has been more time to evaluate response to TB treatment
Problematic Risk may be decreased

Ability to determine Complex because of the large the cause of adverse number of medications started events in a short time period and overlapping side effects profiles
Drug-drug interaction Severe immune reconstitution inflammatory events HIV disease progression (new OI or death Problematic Risk may be increased

Risk may be decreased

Risk may be increased

Burman WJ. Clin Chest Med 2005;26:283-294

TB regimens terapi SAMA (kec. Thiacetazon) antara HIV (-) dan (+) SEGERA!! HIV bhubungan dengan peningkatan mortaliti pberian ART SEGERA Pasien dengan sputum BTA (-) mortaliti lebih tinggi dibandingkan pasien dengan sputum BTA (+)

CD4 < 50 ART 2 mg setelah th/ OAT CD4 > 50 dengan klinis berat ART 2 4 mg setelah th/ OAT CD4 > 50 dgn klinis ringan sedang ART dpt ditunda 2 4 mg tetapi harus dimulai 812 mg setelah th/ OAT Pd psn HIV-MDR/XDR TB ART 2 4 mg sesudah diberikan th/ TB second line.

PIs and RIF: Not Recommended Rifampicin decreases blood levels of all PIs
Protease Inhibitor Effect of Rifampicin

Saquinavir
Ritonavir Indinavir Nelfinavir

by 84%
by 35% by 89% by 82%

Amprenavir Lopinavir/ritonavir

by 81% by 75%

Rifabutin dpt diberikan bersamaan dng ART PIs based regimen drug interaction < Rifapentine TIDAK direkomendasikan pada psn HIV yg sedang mkonsumsi ART unt th/ TB. IRIS dpt terjadi setelah pemberian ART ART & Th/ TB tetap dilanjutkan

In TB/HIV co-infection, ART should be initiated earlier (CD4< 350 cells/mm3), if possible during the induction phase of TB treatment (i.e. between 2 weeks and 2 months) in order to reduce mortality, particularly in patients with low CD4 cell counts.

For patients presented with CD4 < 200 cells/mm3, treatment should be initiated as soon as it is tolerated. 2NRTI + EFV is recommended as the preferred 1st line approach in these patients.
If EFV is not available, causes severe toxicity, or is contraindicated, triple nukes or NVP-based regimens are the recommended alternatives. There are limited PI options for 2nd line ART in patients being concomitantly treated for TB with rifampicin. Use of additional amounts of boosted ritonavir with some PIs (SQV/r or LPV/r) or replacement of rifampicin with rifabutin are the major options.

WHAT CONCURRENT ART REGIMEN TO USE

2 NRTI/NtRTIs plus NNRTI or PI

Recommended dose of ARVs with rifampin
Efavirenz (the preferable) ?600 mg or 800 mg daily
Nevirapine 200 mg bid (or 300mg bid*) Saquinavir/ritonovir 400/400 mg bid or 1000/100 mg bid*

Lopinavir/ritonovir 400/400 mg bid* Maraviroc 600 mg twice-daily (increased dose)

Raltegravir 400 mg twice daily (no change)
CDC treatment guidelines for HIV-TB, Dec 2007
*use with caution

2 NRTI/NtRTIs plus 3rd ARV

PI LPV/r, ATV/r, fAPV/r, SQV/r (standard doses) Atazanavir 400 mg qd Fosamprenavir 1400 mg bid Indinavir 1000 mg tid Nelfinavir 1000 mg tid Maraviroc or raltegravir (no change) Rifabutin dose 150 mg qod or 300 mg 3X/W* 150 mg qd or 300 mg 3XW 150 mg qd or 300 mg 3XW 150 mg qd or 300 mg 3XW 150 mg qd or 300 mg 3XW No change

*associated with TB treatment failure and rifamycin resistance

2 NRTI/NtRTIs plus NNRTI

NNRTI Nevirapine 200 mg bid Efavirenz 600 mg qd Rifabutin dose 300 mg qd or 300 mg 3X/week 600 mg qd or qod

Pill burden Overlapping drug toxicities Pharmacokinetic drug-drug interactions Increased risk of immune reconstitution inflammatory syndrome

Burman WJ. CFAR Symposium 2005, Boston

Burman WJ. CFAR Symposium 2005, Boston

Side Effect
Skin rash*

TB Drug
PZA, RIF, INH

ARV
Nevirapine Efavirenz Abacavir
Zidovudine Ritonavir Amprenavir Indinavir

Nausea, vomiting

PZA, RIF, INH

* May also see rash with cotrimoxazole

Burman et al, Am J Respir Crit Care Med 2001

Side Effect

TB Drug

ARV

Hepatitis

Nevirapine Protease inhibitors PZA, RIF, INH IRIS (with chronic hepatitis) RIF Zidovudine

Leukopenia, anemia

Burman et al, Am J Respir Crit Care Med 2001

Niemi M, et al. Clin Pharmacokinet 2003;42:819-850

Rifampin is a potent inducer of cytochrome P-450 drug metablozing enzymes Rifabutin has less effect on CYP3A4 Rifampin is the only rifamycin in TB endemic areas

Immune reconstitution inflammatory syndrome (IRIS)

Paradoxical worsening of TB symptoms on TB plus HIV therapy Incident TB (unmasked TB) within 4 months of starting ART in HIV-infected patients Immunopathological response to treatment

IRIS cont......
Continue or initiate concurrent therapy Symptomatic therapy with NSAIDs or steroids may be necessary Developed in up to 36% of patients if ART

- 7% if no ART

Generally, self-limited, and last 10 - 40 days.

If the reaction is severe: short course of corticosteroid

IRIS cont....
Risk

factors

Disseminated TB Shorter delay between onset of TB and ART

drugs Low baseline CD4 (<50), higher baseline viral load Greater CD4 or viral load response to ART

Timing

of onset

Usually within first 6 weeks of ART (often 23

weeks, but can be months after ART started)

IRIS
Clinical presentation:

Fever Nodal enlargement Worsening pulmonary infiltrates (with or without respiratory symptoms) Local worsening in extrapulmonary sites

Differential diagnosis of IRIS:

TB

treatment failure Drug-resistant TB Other opportunistic (or nonopportunistic) infections Lymphoma, Kaposis sarcoma Hypersensitivity drug reactions ART failure (if symptoms occur late in the course of ART therapy)

 TB

treatment should be continued Exclude TB treatment failure

Adequate
Exclude

treatment and adherence? Drug resistance?

additional/new diagnosis Continue ART (unless life-threatening) Consider NSAIDS, steroids Drainage of lesions

Other Issues in TB/HIV Treatment

(3 of 3)

Patients with TB and HIV infection should also receive cotrimoxazole as prophylaxis for other infections.

Pneumocystis jiroveci pneumonia

Menurunkan risiko : Pneumocystis jiroveci pneumonia (PCP)

Toxoplasma Infeksi bakteri

Menurunkan kematian & perawatan RS Juga efektif melawan:

Pneumococcus, salmonella, nocardia and malaria

All HIV-positive TB patients should receive Cotrimoxazole Preventive Therapy regardless of the CD4 count, for at least the duration of anti-TB treatment. CPT is recommended for all patients with CD4 cell count less than 200 cells/mm3

Persons with HIV infection who, after careful evaluation, do not have active tuberculosis should be treated for presumed latent tuberculosis infection with isoniazid for 6-9 months

TB/HIV berkaitan dengan mortalitas yang tinggi TB meningkatkan progresi HIV HIV meningkatkan progresi TB Skrining TB pd HIV/AIDS kombinasi 3 gejala : BATUK, DEMAM, KERINGAT MALAM OAT pd TB/HIV = TB non HIV CPT meningkatkan survival diterapkan pd semua TB/HIV IPT LTBI pada TB/HIV

Pemberian ART prinsip sesegera mungkin setelah inisiasi OAT (2 4 mg) disesuaikan dengan CD4 dan klinis HAART meningkatkan survival & menurunkan risiko LTBI menjadi TB aktif Regimen HAART yg berbeda diperlukan krn interaksi dengan Rif Rifabutin kombinasi dengan PIs atau NNRTI

TERIMA

KASIH

TB Risk with HIV Infection

Exceptionally high rate of reactivation of latent infection (7-10% per year) Rapid progression to TB following new infection Increased risk begins soon after HIV infection and increases as immunosuppression increases Increased risk is reduced but not eliminated by antiretroviral treatment Increased potential for reinfection after successful treatment for TB

Progression on TB/HIV Treatment

HIV+ case with TB dx; TB treatment begun

After 2 mo. TB treatment, begins ART

6 wks. later symptoms and CXR worsen

What could be happening here?

Implications of HIV for TB treatment in PLWHA

Treatment is the same, except for the use of Thioacetazone Increased risk of adverse drug reactions Monitor to identify and treat O I during TB treatment Increased case fatality rate, but response in survivors is similar to HIV (-) patients Recurrence of TB after completion of treatment is higher in HIV (+): 5-10% Risk of developing resistance to R, if CD4 < 100 /mm3 Drug interactions: R with ARV

When start ARV treatment in TB patients?

TB patient

HIV (-)

HIV (+)

CD4< 200 / mm3

CD4 200-350/mm3

CD4>350 / mm3

CD4 No available

Start ARV 2weeks-2months

Start ARV After initial phase

Delay ARV

Rifabutin on WHO Essential Medicines List

Rifabutin as part of TB treatment (replacing rifampicin), in HIV-infected patients treated with ritonavir-boosted Protease-Inhibitor containing antiretroviral therapy. Rifabutin
equally safe and effective as rifampicin little effect on PI serum concentrations cost-effective when used in combination with the standard dose of boosted-PIs.

Listed on WHO EML for use with HIV+ patients on second line ART

Earlier ART in context of TB/HIV:

Why is it still challenging in real practice?
0.15

Annual incidence in AIDS cases

Major cause of early mortality in patients using ART in RLS (TB as a priority population for earlier ART) ART significant reduce the occurrence of TB disease, but in RLS the need to treat both diseases at same time is very common TB still an important condition, even in patients using ART and higher CD4 cell count

TB among AIDS patients in Brazil

0.10

Pulmonary TB

Disseminated TB
0.05

Mono
0.00 1985

Dual
1990

Triple therapy
1995 2000

www.aids.gov.br/boletim/bol_htm/boletim.htm

Major challenges of concomitant ART and TB therapy

GI tolerability High pill burden Overlapping toxicities (eg: d4T and INH) IRIS management pK interactions, particularly with rifampicin (NVP, PIs)

ART impacts but alone is not enough: Addition of specific TB prevention strategies is part of the solution

Implementation of IPT (20052007)

2005 (10 countries, 26000 cases)

2006 (25 countries, 27000 cases)

2007 (45 countries, 29000 cases)

Progressing but still poor implemented why?

Rifabutin on WHO Essential Medicines List

Rifabutin as part of TB treatment (replacing rifampicin), in HIV-infected patients treated with ritonavir-boosted Protease-Inhibitor containing antiretroviral therapy. Rifabutin
equally safe and effective as rifampicin little effect on PI serum concentrations cost-effective when used in combination with the standard dose of boosted-PIs.

Listed on WHO EML for use with HIV+ patients on second line ART

Earlier ART in context of TB/HIV:

Why is it still challenging in real practice?
0.15

Annual incidence in AIDS cases

Major cause of early mortality in patients using ART in RLS (TB as a priority population for earlier ART) ART significant reduce the occurrence of TB disease, but in RLS the need to treat both diseases at same time is very common TB still an important condition, even in patients using ART and higher CD4 cell count

TB among AIDS patients in Brazil

0.10

Pulmonary TB

Disseminated TB
0.05

Mono
0.00 1985

Dual
1990

Triple therapy
1995 2000

www.aids.gov.br/boletim/bol_htm/boletim.htm

Major challenges of concomitant ART and TB therapy

GI tolerability High pill burden Overlapping toxicities (eg: d4T and INH) IRIS management pK interactions, particularly with rifampicin (NVP, PIs)

ART impacts but alone is not enough: Addition of specific TB prevention strategies is part of the solution

Implementation of IPT (20052007)

2005 (10 countries, 26000 cases)

2006 (25 countries, 27000 cases)

2007 (45 countries, 29000 cases)

Progressing but still poor implemented why?

If CD4 count not available:

When to Start Antiretrovirals

ART
Start ART as soon as TB rx tolerated Start ART after the intensive phase of TB rx Defer ART until TB rx done

Clinical Presentation
Any pulmonary TB and signs of advanced HIV, or no clinical improvement; extrapulmonary TB
Smear-negative pulmonary TB, gaining weight on rx, no other signs/sx of advanced HIV Smear-positive pulmonary TB, gaining weight on rx, no other signs/sx of advanced HIV

TB/HIV: Adherence
Increased difficulties for adherence: Higher pill burden Greater number of potential drug side effects Dual social stigma Additional illness (opportunistic infections) Difficult medical access, drug-supply

Infection Control
Infection Control: Important in
facilities providing services for patients with TB, especially in high HIV prevalence areas

Establish an infection control plan Maximize natural ventilation of patient care and waiting areas Identify and separate coughing patients Ensure rapid sputum smear results (24 hours) Consolidate TB services in time and

Drug interactions: R with ARV

Mechanism: R stimulates the activity of cytochrome P450 liver enzyme system. P450 liver enzyme system metabolizes PIs and NNRTIs
PIs: SQV, RTV, IDV, NFV NNRTIs: NVP, EFV, DLV

Summary
TB increases HIV progression HIV increases TB progression Standard TB treatment usually cures TB in TB/HIV Despite successful TB treatment, mortality among TB/HIV patients remains high All HIV/TB patients qualify for cotrimoxazole prophylaxis and it improves survival

Summary (2)
HAART for eligible patients greatly improves survival Different HAART regimens may be required because of drug interactions with rifampicin Programmatic synergy between the TB and HIV programs is needed to improve treatment of both conditions and will reduce disease and death

Summary: TB/HIV Treatment

Summary:
Standard TB treatment usually cures TB in TB/HIV co-infection Despite successful TB treatment, mortality among TB/HIV patients remains high Cotrimoxazole prophylaxis (CPT) improves survival and should be used in all TB/HIV patients Latent TB infection should be treated with isoniazid (IPT) in HIV-infected patients

Summary: TB/HIV Treatment

Summary
(continued):

ART for eligible patients greatly improves survival Different ART regimens may be required because of drug interactions with rifampicin Coordination between the TB and HIV programs is needed to improve treatment of both conditions and will reduce disease and death

Standard 8: All patients who have not been previously treated should receive an internationally accepted treatment regimen. Initial phase: 2 months INH, RIF, PZA, EMB. Continuation phase: 4 months INH and RIF. EMB may be omitted in the initial phase for non-HIV smear-negative cases without severe disease. * Abbreviated versions The doses of anti-TB drugs used should

Summary: ISTC Standards Covered*

Summary: ISTC Standards Covered*

Standard 15: All TB/HIV patients should be evaluated to determine if ART is indicated during the course of TB treatment. Appropriate arrangements for access to ART should be made. However, initiation of treatment for tuberculosis should not be delayed. TB/HIV patients should also receive cotrimoxazole preventative * Abbreviated versions therapy.

Summary: ISTC Standards Covered

Standard 16:
Persons with HIV infection who, after careful evaluation, do not have active tuberculosis should be treated for presumed latent tuberculosis infection with isoniazid for 6-9 months

The Effects of HAART on TB Progression

Highly Active Anti-retroviral Therapy (HAART) alone can reduce the risk of latent TB infection progression to active TB disease by as much as 80%92%

Source: TB/HIV: A Clinical Manual. Second Edition. WHO, 2004

ISTC Standard 12
In areas with a high prevalence of HIV infection in the general population where tuberculosis and HIV infection are likely to co-exist, HIV counseling and testing is indicated for all tuberculosis patients as part of their routine management. In areas with lower prevalence rates of HIV, HIV counseling and testing is indicated for TB patients with symptoms and/or signs of HIV-related conditions and in tuberculosis patients having a history suggestive of high risk of HIV exposure.

ART and RIF-based TB Rx

Recommended ART regimen:
Efavirenz plus two nucleosides (EFV + two NRTIs)
Use efavirenz for adults and children >3 years old Avoid 1st trimester of pregnancy Efavirenz dose 600mg (or 800mg)

NNRTIs and Rifampicin

Rifampicin decreases blood levels of NVP and EFV
NNRTI Effect of Rifampicin

Nevirapine
Efavirenz

3758%

22%

ART and RIF-based TB Rx

Choice of nucleosides (NRTIs) to combine with efavirenz:
Usual adult first-line therapy (may also be used in children >3):
Zidovudine + lamivudine (AZT/3TC) Alternative in case of anemia: Stavudine + lamivudine (d4T/3TC)

ART Options: RIF-based TB Rx

More options (consider expert consultation):
Not as potent, but no drug interactions WHO first-line for children >3
Nevirapine + 2 NRTIs

Triple NRTI: abacavir or tenofovir* + 2 NRTIs

Some successful clinical experience Concern for low blood levels, toxicity overlap (hepatitis, rash), and *Tenofovir not recommended in pregnancy hypersensitivity reactions

ART Options: RIF-based TB Rx

Ritonavir boosting of other PIs can achieve adequate blood levels but significant hepatotoxicity risk

Can be used in children (<3) Lopinavir/ritonavir (Kaletra) usual dose 400/100 mg twice a day PLUS an extra ritonavir 300 mg twice a day (adult dose)