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The New Strategy in HIV

Treatment
Muchlis Achsan Udji Sofro
KSM Penyakit Dalam RSUP Dr Kariadi- FK UNDIP
PIT PAPDI 2018

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Pendahuluan
• Infeksi HIV-AIDS masih merupakan problem global
• 35 juta orang hidup dengan HIV-AIDS,
• 2017: 970.000 orang meninggal karena infeksi HIV.
• Infeksi HIV di Indonesia setiap tahun selalu meningkat
• Jumlah kasus HIV s/d Maret 2017, terdiagnosis 242,699 kasus
• 40,000-an kasus ditemukan per-tahun
• +110 kasus per hari

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Primary HIV Infection: Pathogenesis

CD4 Cell Count (cells/mm³)


Plasma HIV RNA (copies/mL) 10,000,000 Symptoms
1,000,000

100,000
Plasma RNA Viral Load
10,000

1,000
1,000
100
CD4 Cell
10 500
Count

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4-8 Weeks Up to 12 Years 2-3 Years

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Diagnostic Testing for PHI

HIV-1 Antibodies
1 mil
HIV RNA

HIV RNA
100,000 +
_
10,000
Ab
1,000 P24 +

100 Exposure
Symptoms
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0 20 30 40 50
Days 9
Primary HIV Infection: Pathogenesis
Anti-HIV Sero-conversion
T-cell response Antibody response

CD4 count (cells/mm³)


10,000,000
Plasma HIV RNA (copies/mL)

1,000,000

100,000
Plasma RNA Viral Load
10,000

1,000 Viral set point


1,000
100
CD4 Cell
10 500
Count

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4-8 Weeks Up to 12 Years 2-3 Years

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A lot of important stuff happens here
From Antigen-Presenting Cell (APC)
to CD4 Cell Destruction

APC CD4 Cell Activated CD4 Cell

HIV HIV Picture

Adapted from: Cohen DE, Walker BD. Clin


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Infect Dis 2001;32:1756-68
Loss of HIV-specific Cytotoxic
T-Lymphocyte Response (CTL)
HIV CD4 Cell Activated CD4 Cell HIV-Infected CD4

Antigen-Presenting Cells Lymphokines

HIV CD8 Cell Activated CD8 Pre CTLPicture


Mature CD8 CTL

Adapted from: Cohen DE, Walker BD. Clin


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Infect Dis 2001;32:1756-68
Cellular Immune Response to Acute HIV Infection

Acute HIV

100
Weak CTL
80 Rapid Progression
HIV RNA

60
Moderate CTL
Moderate Progression
40

20 Strong CTL
Slow Progression
0
0 1 2 3 4 5Time6 7 8
6 months

From: Walker BD. Nature 2000;407:313-4. 13


Slide courtesy David Spach, MD
• Memulai ARV sedini mungkin dapat mempertahankan sel T CD4, 
• meningkatkan kemampuan CTL terhadap HIV.

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Structured Treatment Interruptions

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HIV Testing Occurs in a Variety of Settings

T&C

ANC
Blood Provide ARV
Banks
treatment to
Prevent HIV Surveillance
HIV-infected
Infections persons
TB Clinics

Hospitals
Provide care
to HIV-affected
STI Clinics persons

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Lab workers Health workers Counselors
Spectrum of HIV Tests
• HIV diagnosis (Antibody/Antigen testing)
• Enzyme Immunoassays (EIAs)
• Rapid tests
• Western blot (WB)
• Early diagnosis in infants
• p24
• Initiation and monitoring of ART
• CD4
• Viral Load

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Lab workers Health workers Counselors
Challenges of HIV Testing
• Early detection of seroconversion
• Early detection in infants born to HIV positive mothers
• Effect of HIV subtypes on test performance
• Impact of other health conditions on test performance
• Product specific equipment
• Technical skill

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Lab workers Health workers Counselors
Enzyme Immunoassays (EIAs)
• Quantitative assay to measure HIV antibodies
• Most detect antibodies to HIV-1 and HIV-2
• Antigens coated in microwells
• HIV Antigen / Antibody reaction is detected by color change
• Intensity of color reflects amount of antibody present serum
• Some assays can detect both HIV antibody and HIV antigen (close
window period)
• Issues:
• Skilled lab technician
• Large volume testing
• Properly maintained equipment required

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Lab workers Health workers
Enzyme ImmunoAssays (EIAs) – Cont’d

After several incubation and wash steps, a An automated reader gives a


color reaction occurs if HIV antibody is measurement of optical density
present (presence of color) for each well
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Lab workers Health workers
HIV Rapid Tests
• Qualitative assay to detect HIV antibodies
• Most detect HIV 1 and HIV 2
• As reliable as EIAs
• Issues:
• Small volumes
• Validation of use
• Appropriate training

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Lab workers Health workers
WHO
Kemenkes
Urin
Darah
Tes Cepat

Air Liur

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Western Blot / Line Immunoassays
• Used as supplemental test for
confirmation (only difficult cases)
• Detects antibodies to specific HIV
antigens on cellulose strip
• Issues:
• Multiple standards for
performance and interpretation
• Expensive
• Limited commercial availability

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Lab workers Health workers
HIV p24 Antigen
• Core protein of the virus
• EIA detects p24 antigen before antibody can be detected
 Detected 2 to 3 weeks after HIV infection
 Detected about 6 days before antibody tests become reactive
• Used for:
• Diagnosis of pediatric HIV-1 infections
• Blood bank safety (high incidence countries)
• Issues:
• Level 4 complexity
• Properly maintained equipment required

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Lab workers Health workers
CD4 T-Lymphocyte
• CD4 T-lymphocyte counts used for:
• Determining clinical prognosis
• Assessing criteria for antiretroviral therapy
• Monitoring therapy
• Manual and automated methods
• Issues:
• Requires high level of technical skill for test
performance and interpretation
• Properly maintained equipment

Lab workers Health workers


Viral Load
• Quantitative molecular assay measures amount of HIV in blood
products
• Used to:
• Predict disease progression
• Assist with deciding when to initiate anti-retroviral therapy
• Monitors response to anti-retrovirals
• Issues:
• Expensive
• Labor-intensive
• Special facilities

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Lab workers Health workers
25-4-2018
Ibu hamil aterm di RB Swasta
Tes HIV di Lab Swasta
Hasil tes HIV Reaktif

Dirujuk ke RSUP Dr Kariadi


Dipersiapkan operasi Secar
Status Ibu HIV Positif

Stres  Depresi
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30 April 2018 (dua hari sejak tes pertama) Ibu boleh Menyusui
Tes HIV ulang di RSUP Dr Kariadi
Dengan 3 Reagen yang Berbeda ARV tidak diberikan
Hasil non Reaktif
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Pasien di sarana rawat jalan dan rawat inap
Kelompok pasien yang di tes HIV
 LSL, Waria, WPS/PPS, Penasun dan Pelanggan
 Ibu hamil
 Pasien TB
 Pasien IMS atau dengan keluhan IMS
 Pasien hepatitis
 Pasien dengan gejala penurunan kekebalan tubuh
 Pasangan ODHA Berikan verbal consent
 Di Tanah Papua, semua orang yang datang ke
layanan

Menerima Tes Menolak tes

Ke laboratorium Tanda tangan surat pernyataan, beri informasi manfaat tes

Hasil lab baik reaktif atau neg dikembalikan ke nakes pengirim

Reaktif Inkonklusif Negatif

Jelaskan makna hasil tes, jelaskan secara garis besar, apa langkah yang
akan dilakukan di klinik terpadu untuk akses layanan ARV beserta semua
paket perawatan 34
Hasil Tes : Indeterminate:
• dua tes reaktif
• 1 tes reaktif dengan risiko atau pasangan berisiko
• >>>Tes diulang 2 minggu lagi dengan sampel berbeda,
• jika tetap indeterminate, lanjutkan dengan PCR
• >>>Jika tidak ada PCR,
• rapid test diulang 3, 6, dan 12 bulan dari pemeriksaan yang pertama.
• Jika sampai satu tahun hasil tetap indeterminate dan faktor risiko rendah,
hasil dapat dinyatakan sebagai negatif

PMK No. 87 tahun 2014 tentang Pedoman Pengobatan Antiretroviral


PMK No. 15 tahun 2015 tentang Laboratorium HIV dan Infeksi Oportunistik
Patologi Klinik, 2018 35
Bagaimana dengan Terapi ARV?

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DHHS, IAS-USA Guidelines:
Recommended Regimens for First-line ART
Class DHHS[1] IAS-USA*[2]
INSTI  BIC/TAF/FTC
 DTG/ABC/3TC  DTG/ABC/3TC
 DTG + (TAF or TDF)/FTC  DTG + TAF/FTC
 EVG/COBI/(TAF or TDF)/FTC  EVG/COBI/TAF/FTC
 RAL + (TAF or TDF)/FTC  RAL + TAF/FTC
Bold text identifies single-tablet regimens. *IAS-USA guidelines not updated since the approval of BIC/TAF/FTC.

• Recommendations may differ based on BL HIV-1 RNA, CD4+ cell count, CrCl, eGFR,
HLA-B*5701 status, HBsAg status, and osteoporosis status
• With FDA approval of 1200-mg RAL,[3] all options now available QD (except in
pregnancy)

1. DHHS guidelines. March 2018. 2. Günthard HF, et al.


JAMA. 2016;316:191-210. 3. Raltegravir [package insert]. 2018. Slide credit: clinicaloptions.com
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Paduan ART Lebih mudah dan sederhana

Jenis ART Lebih mudah dan sederhana

Dewasa dan anak usia >5 tahun Anak usia <5 tahun

Mulai dengan salah satu paduan

TDF + 3TC + EFV Pilihan Pilihan NRTI Pilihan


Pilihan (kombinasi dosis NRTI ke-2 NNRTI
tetap/KDT) ke-1
TDF + 3TC (atau FTC) + Zidovudin
(AZT) Nevirapin
NVP
Stavudin Lamivudin (NVP)
alternatif AZT + 3TC + EFV (d4T) (3TC)
Tenofovir Efavirenz
AZT + 3TC + NVP
(TDF) (EFV)
Sudah dalam terapi lini pertama
Teruskan paduan yang sudah digunakan Kemenkes RI, 2014 39
Recommendations
WHO Guideline ARV 2017
• Rapid ART initiation should be offered to all people living with HIV
following a confirmed HIV diagnosis and clinical assessment.
• (Strong recommendation: high-quality evidence for adults and
adolescents; low-quality evidence for children)
• a Rapid initiation is defined as within seven days from the day of HIV
diagnosis; people with advanced HIV disease should be given priority for
assessment and initiation.
• ART initiation should be offered on the same day to people who are
ready to start.
• (Strong recommendation: high-quality evidence for adults and
adolescents; low-quality evidence for children)

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Timing of ART for people with TB
• Routine TB symptom screening for people with HIV, using an
algorithm containing fever, cough of any duration, weight loss and
night sweats,
• will help to identify people who should either be expedited for TB diagnosis
(if symptoms)
• or given preventive TB therapy (if no symptoms)

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• TB treatment should be initiated first, followed by ART as soon as
possible within the first eight weeks of treatment (strong
recommendation, high-quality evidence).
• TB patients4 living with HIV who have severe immunosuppression
(such as CD4 cell counts <50 cells/mm3) should receive ART within
the first two weeks of initiating TB treatment.
• Caution is needed for people living with HIV with TB meningitis, since
immediate ART is associated with more severe adverse events than
initiating ART two months after the start of TB treatment.

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Timing of ART for people with cryptococcal
meningitis (WHO, Guideline, 2017)
• Immediate ART initiation is contraindicated among people living with HIV
with cryptococcal meningitis because of the risk of life-threatening immune
reconstitution inflammatory syndrome (conditional recommendation, low-
quality evidence).6
• ART initiation should be deferred until there is evidence of a sustained
clinical response to antifungal therapy and after four weeks of induction
and consolidation treatment with amphotericin B–containing regimens
combined with flucytosine or fluconazole or after 4–6 weeks of treatment
with a high-dose fluconazole induction and consolidation regimen
(conditional recommendation, low-quality evidence).
• For people with signs and symptoms of meningitis, ART should be delayed
pending the results of lumbar puncture.
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Pemantauan kegagalan terapi

WHO, 2017

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Klinis:
Timbang BB
Infeksi Oportunistik

Monitoring CD4: tiap 6


CD4: tiap 6 bulan:
terapi ARV bulan:
> 400 sel/mm3
> 400 sel/mm3

Viral Load: tiap tahun:


Tidak terdeteksi

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Viral Load TERDETEKSI

• Menunjukkan proses pengobatan sedang berlangsung


• Virus mulai tidak mempan dengan obat ARV

• Sebagian pil tidak terminum karena:


• “lupa”
• “Malas”
• “Bosan”
• “berhenti minum obat”  “merasa sudah sehat”

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2 th Terapi ARV
Berpotensi “drop out”

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Klinis:
- Infeksi oportunistik baru/ kambuh
- Ditemukan AIDS stadium 3 atau 4

Imunolgis:
GAGAL - CD4 menetap < 100 sel/mm3
- Turun > 50% dari nilai tertinggi
TERAPI

Virologis:
- Viral load > 1000 kopi/ml 2x pemeriksaan
- Selang 3-6 bulan

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The Cause of Treatment Failure
Social/Personal Issues
Regimen Issues
Toxicities

- Poor Potency
Poor Adherence
- Wrong Dose
- Host Genetics
- Poor Absorption
Insufficient Drug Level
- Rapid Clearance
- Poor Activation
- Drug Interactions
Viral Replication in the
Presence of Drug

Resistant Virus Transmission

Treatment Failure
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Criteria of treatment failure / resistance

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Management of ARV Failure
First-line regimen failure Second-line regimen failure
and beyond
Failing regimen (+ NRTI) PI susceptible
 Boosted PI Reinforce adherence
Modify for convenience or toxicity No‡
Yes
 NNRTI Boosted PI + NRTIs
Boosted PI + INSTI
Boosted PI + NRTIs 2 (preferably 3)
DTG + NRTIs (if 1 fully active)
Boosted PI + active INSTI fully active drugs
Boosted PI + NRTIs (or partially active drug if no
 INSTI
Boosted PI + active INSTI* other options)
DTG + NRTIs (≥ 1 fully active)†

*If RAL or EVG resistance detected, DTG + boosted PI can be used if DTG susceptible.
†In setting of no INSTI resistance.
‡Rare in patients never exposed to unboosted PI.

DHHS guidelines. March 2018. Slide credit: clinicaloptions.com


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Terimakasih

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